Skip to main content
Erschienen in: Molecular Brain 1/2009

Open Access 01.12.2009 | Research

A novel mechanism of hippocampal LTD involving muscarinic receptor-triggered interactions between AMPARs, GRIP and liprin-α

verfasst von: Bryony A Dickinson, Jihoon Jo, Heon Seok, Gi Hoon Son, Daniel J Whitcomb, Ceri H Davies, Morgan Sheng, Graham L Collingridge, Kwangwook Cho

Erschienen in: Molecular Brain | Ausgabe 1/2009

Abstract

Background

Long-term depression (LTD) in the hippocampus can be induced by activation of different types of G-protein coupled receptors, in particular metabotropic glutamate receptors (mGluRs) and muscarinic acethycholine receptors (mAChRs). Since mGluRs and mAChRs activate the same G-proteins and isoforms of phospholipase C (PLC), it would be expected that these two forms of LTD utilise the same molecular mechanisms. However, we find a distinct mechanism of LTD involving GRIP and liprin-α.

Results

Whilst both forms of LTD require activation of tyrosine phosphatases and involve internalisation of AMPARs, they use different molecular interactions. Specifically, mAChR-LTD, but not mGluR-LTD, is blocked by peptides that inhibit the binding of GRIP to the AMPA receptor subunit GluA2 and the binding of GRIP to liprin-α. Thus, different receptors that utilise the same G-proteins can regulate AMPAR trafficking and synaptic efficacy via distinct molecular mechanisms.

Conclusion

Our results suggest that mAChR-LTD selectively involves interactions between GRIP and liprin-α. These data indicate a novel mechanism of synaptic plasticity in which activation of M1 receptors results in AMPAR endocytosis, via a mechanism involving interactions between GluA2, GRIP and liprin-α.
Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1756-6606-2-18) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

BAD conducted electrophysiology. JJ participated in the electrophysiology experiments. HS designed and participated in molecular experiments. GHS conducted molecular experiments. DJW participated in electrophysiology. CHD participated production of the M1 agonist. MS, GLC and KC conceived the original concept of this study and wrote the manuscript. KC supervised the entire project. All authors read and approved the final manuscript.

Background

Cholinergic neurotransmission in the brain has a critical role in cognition [14]. In particular, inhibition of muscarinic receptors produces pronounced amnesia and loss of cholinergic innervation is an early feature of Alzheimer's disease (AD) [58]. As a result, the primary treatment for the cognitive deficits in AD is cholinesterase inhibitors, used to increase the amount of ACh available to activate neurons. In addition, there is increasing interest in the use of agents that specifically activate muscarinic AChRs (mAChRs) for the treatment of both AD [911] and schizophrenia [12]. It is therefore extremely important to understand how ACh regulates synaptic function, particularly that which is relevant to learning and memory.
In this context, activation of mAChRs using carbachol (CCh) induces LTD of excitatory synaptic transmission in various brain regions, including the visual cortex [1315], perirhinal cortex [16, 17] and hippocampus [13, 1821]. However, the molecular mechanisms of mAChR-dependent LTD are poorly understood. In the present study we have therefore investigated the mechanisms involved in CCh-induced LTD (mAChR-LTD) in the hippocampus of adult rats. We find that activation of M1 receptors results in an LTD that is dependent on the activity of protein tyrosine phosphatases (PTPs), but is independent of Ca2+, PKC, serine/threonine protein phosphatases and protein synthesis. In all of these respects, this form of LTD is the same as that induced by activation of mGlu5 receptors in hippocampal slices obtained from adult animals [22, 23]. However, to our surprise, we found that mAChR-LTD, but not mGluR-LTD, involves interactions between GRIP and the AMPAR subunit GluA2 (IUPHAR nomenclature for subunits previously known as GluR2 or GluRB; see [24]). Furthermore, mAChR-LTD also selectively involves interactions between GRIP and liprin-α. These data indicate a novel mechanism of synaptic plasticity in which activation of M1 receptors results in AMPAR endocytosis, via a mechanism involving interactions between GluA2, GRIP and liprin-α.

Results

Carbachol induces an NMDAR-independent form of LTD in the CA1 area

Bath application of carbachol (CCh; 50 μM, 10 min) resulted in LTD of synaptic transmission in the CA1 region of the hippocampus in 4–5 week old rats (56% ± 7% of baseline, quantified 30 min following washout of CCh; n = 8) (Figure 1A). A similar LTD was induced when CCh was applied in the presence of an NMDAR antagonist, D-AP5 (58% ± 5%, n = 9) (Figure 1B), demonstrating that this is an NMDAR-independent form of synaptic plasticity. The AChR-LTD involved activation of M1 receptors, since it was significantly reduced by pirenzepine (0.5 μM) (88% ± 7%, n = 5 [p < 0.05 vs control LTD]) (Figure 1C). In addition, the M1 selective agonist 77-LH-28-1 (10 μM) induced a slow-onset LTD (60% ± 8%, n = 6) (Figure 1D) that was also resistant to treatment with D-AP5 (61% ± 7%, n = 5) (Figure 1E) and was blocked by pirenzepine (93% ± 11%, n = 7 [p < 0.05 vs control]) (Figure 1F). The CCh-induced LTD resembles that induced by group I mGluRs and so could conceivably be due to CCh facilitation of endogenous L-glutamate actions on group I mGluRs. However, this was not the case, since CCh-induced LTD was completely resistant to inhibitors of group I mGluRs (58% ± 13%, n = 6) (Figure 1G).
To investigate the expression mechanism of this mAChR-LTD, we performed surface biotinylation assays using hippocampal slices. Hippocampal slices were treated with CCh, in the presence or absence of pirenzepine, and the cell surface and total expression level of GluA2 subunits was compared. CCh induced a substantial internalisation of GluA2 subunits (Figure 1H), consistent with a mechanism that involves the internalisation of AMPARs [20].

Signalling mechanisms involved in mAChR-LTD

M1 receptors conventionally signal via IP3-induced Ca2+ release from intracellular stores and/or activation of PKC [2528]. However, intracellular infusion of cyclopiazonic acid (CPA, 2 μM), which depletes Ca2+ stores, had no effect on mAChR-LTD (52% ± 6%, n = 6) (Figure 2A). Similarly, postsynaptic infusion of either the PKC inhibitor Ro 32-0432 (10 μM, 53% ± 7%, n = 6) (Figure 2B) or the inhibitory peptide PKC19–31 (10 μM; 64% ± 7%, n = 9) (data not shown) had no effect on mAChR-LTD. Therefore, it would seem that mAChR-LTD involves an unconventional signalling mechanism. An alternative possibility is that mAChR-LTD involves a different Ca2+-dependent process, since most forms of synaptic plasticity are Ca2+-dependent [29]. However, postsynaptic infusion of BAPTA (10 mM) had no effect on mAChR-LTD (61% ± 9%, n = 9) (data not shown).
The serine/threonine protein phosphatases PP1 and PP2B (calcineurin) are required for NMDAR-dependent LTD [30, 31]. To determine whether these enzymes are important for mAChR-LTD we included either okadaic acid or cyclosporin-A in the whole-cell solution. However, neither okadaic acid (100 nM, 66% ± 8%, n = 5) (Figure 2C) nor cyclosporin-A (10 μM, 64% ± 7%, n = 7) (data not shown) had any effect on mAChR-LTD. Another candidate mechanism for mAChR-LTD involves protein synthesis [16, 20]. Therefore it was surprising to find that neither of the protein translation inhibitors anisomycin (20 μM, 68% ± 7%, n = 7) (Figure 2D) nor cycloheximide (80 μM, 70% ± 8%, n = 7) (data not shown) had any significant effect on mAChR-LTD.
These negative findings are reminiscent of mGluR-LTD in the CA1 region of the hippocampus of adult rats [22, 23]. Since this latter form of LTD is blocked by broad spectrum PTP inhibitors, we tested orthovanadate and phenylarsine oxide (PAO) on mAChR-LTD. Both orthovanadate (100 μM, 101% ± 5%, n = 5) (Figure 2E) and PAO (1.5 μM, 93% ± 7%, n = 7) (data not shown) blocked mAChR-LTD. Finally, we tested whether, like mGluR-LTD [32], mAChR-LTD requires activation of G-proteins or whether it operates in a G-protein independent manner (see [33]). Postsynaptic inclusion of guanosine-5'-O-(2-thiodiphosphate) (GDPβS) inhibited mAChR-LTD (1 mM, 91% ± 6%, n = 6) (Figure 2F), confirming that a G-protein signalling mechanism is involved. These results, which are summarised in Figure 2G, show that mAChR-LTD involves very similar signalling mechanisms to that previously described for mGluR-LTD in adult hippocampus [22, 23, 32].

An interaction between GluA2 and GRIP is necessary for mAChR-LTD

How activation of PTPs results in LTD is not known, but the finding that both mGluR-LTD and mAChR-LTD involve internalisation of AMPARs suggests that proteins that interact with these receptors might be involved. In the ventral tegmental area (VTA) it has been shown that blocking the interaction between GluA2 and PICK1, with the peptide inhibitor pep2-EVKI (YNVYGIEEVKI) [34, 35], prevents mGluR-LTD [36]. In addition, blocking GluA2 interactions with PICK1 also prevents mGluR-LTD in the cerebellum [37]. We therefore included pep2-EVKI (100 μM) in the whole-cell solution and compared its effects with that of a control peptide, pep2-SVKE (100 μM), which has no effect on GluA2-PDZ interactions [34, 35]. We found that neither pep2-EVKI (64% ± 6%, n = 9) (Figure 3A) nor pep2-SVKE (67% ± 13%, n = 6) (Figure 3A) had any effect on mAChR-LTD. We therefore tested pep2-SVKI (YNVYGIESVKI), which in addition to blocking PICK1 interactions with GluA2 also blocks GRIP (ABP) interactions with this subunit [34, 35]. We found that pep2-SVKI (100 μM) caused a characteristic run-up in synaptic transmission [35] and, most surprisingly, blocked mAChR-LTD (97% ± 9%, n = 8) (Figure 3B). These interfering peptide experiments suggest that GRIP rather than PICK1 is involved in mAChR-LTD.
Given the identical signalling cascades triggered by both M1 and mGlu5 receptors it was natural to assume that pep2-SVKI should also block DHPG-LTD. Remarkably, however, it did not. Thus, the levels of LTD induced in cells loaded with pep2-SVKE (54% ± 8%, n = 6) (Figure 3C) and pep2-SVKI (61% ± 4%, n = 6) (Figure 3D) were not significantly different. These results demonstrate a divergence at the level of AMPAR trafficking between these two forms of LTD, despite the similarity in signal transduction mechanisms.

GRIP1-Liprin-α association has a critical role in mAChR-LTD

We sought an explanation how GRIP might be involved in mAChR-LTD. In this context, an association between GRIP and liprin-α is important for synaptic targeting of AMPA receptors [38, 39]. Liprin-α directly interacts with GRIP through its PDZ6 domain [38] and it also recruits leukocyte common antigen-related receptor (LAR) to GRIP [39]. LAR is a PTP that is known to be involved in axonal guidance and neuronal development including cholinergic network formation [40, 41]. Therefore we determined whether the GRIP-liprin-α association has a role in mAChR-LTD.
To investigate the potential role of the GRIP-liprin-α association in mAChR-LTD we included a peptide in the patch pipette (TVRTYSC) (100 μM) that corresponds to the C-terminal region of liprin-α, which is the interaction site with the PDZ6 domain of GRIP [38]. We interleaved these experiments with a control peptide (TVRTASC) (100 μM), which is unable to bind to GRIP due to an alanine substitution for tyrosine in the -2 position [38]. Whilst the C-terminal fragment blocked mAChR-LTD (98% ± 9%, n = 6) (Figure 4A) the control peptide did not (59% ± 7%, n = 5) (Figure 4B). To investigate whether the GRIP-liprin-α interaction is specifically required for mAChR-LTD we also investigated both mGluR-LTD and NMDAR-LTD. Interestingly, neither the active (60% ± 8%, n = 7) (Figure 4C) nor control (59% ± 9%, n = 8) (Figure 4D) peptides had any effect on DHPG-LTD. Similarly, the active (62% ± 3%, n = 6) (Figure 4E) and control (62% ± 6%, n = 6) (Figure 4F) peptides were also without effect on NMDA-induced LTD. These data indicate a specific role for the interaction between GRIP and liprin-α in the induction of mAChR-LTD (see Figure 5).

Discussion

In the present study we have investigated a form of LTD involving muscarinic activation that leads to tyrosine dephosphorylation and the removal of AMPARs from the cell surface. Novel aspects of this work include the observations that the process involves interactions between the GluA2 subunit and GRIP and between GRIP and liprin-α, a protein that targets the PTP, LAR to GRIP. Remarkably, LTD induced by group I mGluRs does not utilise this same set of protein interactions, despite being triggered by activation of the same class of G protein and involving similar signal transduction mechanisms. These results point to a hitherto unexpected and remarkable degree of specificity in the protein: protein interactions that are involved in very similar forms of synaptic plasticity.

Receptor mechanisms involved in CCh-LTD

LTD induced by the activation of muscarinic ACh receptors has been described in several brain regions, in particular the hippocampus [13, 1921, 42], visual cortex [1315, 43] and perirhinal cortex [16, 17]. In some instances the LTD is dependent on the activation of NMDARs [13, 19, 43] whilst in others it is not [14, 16, 20]. It is established that stimulation of muscarinic receptors can facilitate the activation of NMDARs [4446]. It is likely therefore that the LTD that is sensitive to NMDAR blockade involves a muscarinic modulation of NMDAR-dependent LTD. In contrast, the LTD that is insensitive to NMDAR blockade is an independent form of LTD. In the present study the LTD that we have studied was of the latter variety since it was unaffected by D-AP5. This LTD resembles that induced by other Gq coupled receptors, such as the extensively characterised LTD induced through the activation of group I mGluRs by DHPG [e.g. [4752]]. Other Gq coupled receptors can also induce LTD [21, 53] suggesting that these neurotransmitters converge at the level of the G-protein with respect to their involvement in LTD. Consistent with previous work, CCh-induced LTD is mediated via activation of M1 receptors [14, 19] whilst the initial depression requires activation of a different muscarinic subtype [19, 42].

Signalling mechanisms involved in mAChR-LTD

We tested a number of different inhibitors of cell signalling pathways to elucidate the pathways that lead from mAChR activation to AMPAR internalisation. In many cases we obtained negative results but this is not due to ineffective inhibition of the target compound. Not only were the inhibitors applied directly to the postsynaptic cell via the patch pipette, at concentrations known to be effective in other experiments, but in most cases we found, during parallel experiments, that the same compounds were effective on other forms of synaptic plasticity (e.g. [54]).
Compared to DHPG-LTD very little is known about the downstream signalling during mAChR-LTD. Classically, stimulation of M1 receptors leads to activation of PKC and the release of Ca2+ from intracellular stores. However, we found no evidence that either limb of this pathway was involved in mAChR-LTD. The lack of effects of PKC inhibitors agree with previous studies of LTD induced by carbachol [14] and DHPG [55, 56]. The effect of interfering with Ca2+ stores is less clear, since a partial inhibition by CPA of CCh-LTD was observed in perirhinal cortex [16]. This might reflect a difference in brain region. In the present study, the LTD studied was also unaffected by BAPTA. This insensitivity to the chelation of intracellular Ca2+ has also been reported for DHPG-LTD [57], and suggests that the signalling pathways involved in these Gq-dependent forms of synaptic plasticity can be Ca2+-independent. Previous work has implicated protein synthesis in mAChR-LTD. In two of these studies the effect of protein translation inhibitors were apparent rapidly but were only partially effective [16, 20] whilst in another study these same inhibitors only affected mAChR-LTD after a delay of more than an hour [14]. In agreement with the latter report, we found no effect of protein translation inhibitors on mAChR-LTD during the duration of our experiments. A similar dichotomy has been reported with mGluR-LTD, with reports of both protein synthesis dependence [49] and independence [23], for reasons that are not clear. In terms of treatments that were effective, we did find that inhibition of PTPs completely prevented the induction of mAChR-LTD. This observation, together with the insensitivity to a serine/threonine protein phosphatase, again highlights similarities between mAChR-LTD and mGluR-LTD [22, 23]. In summary, we can conclude that activation of M1 receptors results in the loss of surface AMPARs and the generation of LTD via a Ca2+-independent signalling cascade that involves one or more types of PTP.

A role for GRIP in mAChR-LTD

Our study has demonstrated that mAChR-LTD induced by carbachol application is dependent on the internalisation of GluA2-containing AMPA receptors (see also [20]). A number of studies have shown that the induction of various forms of LTD involves phosphorylation and dephosphorylation events, which regulate interactions of PDZ domain proteins with AMPA receptors and induce AMPA receptor mobilisation (see, [58]). In particular, endocytosis of GluA2-containing AMPA receptors has previously been suggested to involve the PICK1-GluA2 interaction and a dependency upon PKC phosphorylation of S880 on the GluA2 subunit [5962]. Indeed, there is considerable evidence for a role of PICK1 in mGluR-LTD in a variety of brain regions, including the cerebellum [37, 63, 64], VTA [65] and perirhinal cortex [54]. Surprisingly, therefore, we obtained no evidence for a role of PICK1 in mAChR-LTD in the hippocampus. This observation suggests that despite coupling to the same G-proteins and utilising similar signal transduction methods, mGluR-LTD and mAChR-LTD exploit different mechanisms at the level of AMPAR trafficking.
Whilst we found no evidence for a role of PICK1 in mAChR-LTD, we did find evidence of an essential role for GRIP. Although GRIP, and the related protein ABP, are established as important interactors with AMPARs [35, 59, 66, 67] their precise roles are not known. For example, GRIP has been implicated in the stabilisation of AMPARs at synapses [59, 61, 62] and intracellular organelles [35, 68] as well as in the sorting and transport of AMPARs [69, 70]. Our results suggest that GRIP is also involved in the regulated synaptic removal of AMPARs. Specifically, blocking the interaction of GRIP with GluA2 prevents mAChR-LTD. This suggests that GRIP targets machinery to GluA2 that is involved in their synaptic removal. Remarkably, this effect is not part of a generalised LTD mechanism triggered by Gq-coupled receptor activation since mGluR-LTD was completely unaffected by blockade of the GluA2-GRIP interaction.

A role for liprin-α in mAChR-LTD

An important interactor of GRIP is liprin-α (SYD2). This molecule binds to PDZ6 of GRIP and is involved in the surface expression and synaptic clustering of AMPARs [38]. Whether liprin-α is involved in the acute regulation of AMPAR synaptic expression, as occurs during LTP and LTD, is unknown. Our data, showing that a peptide capable of blocking the interaction of liprin-α with GRIP blocks mAChR-LTD, is consistent with the possibility that liprin-α plays a role in the rapid removal of AMPAR from synapses. Consistent with the unique role of GRIP in mAChR-LTD we found that the peptide designed to block the interaction between GRIP and liprin-α selectively blocks mAChR-LTD, having no effect on two other forms of LTD.
This raises the question as to how liprin-α might be functioning in mAChR-LTD. It is known that liprin-α binds the leukocyte common antigen-related (LAR) family receptor protein tyrosine phosphatase (LAR-RPTP). These PTPs are enriched at synapses and form complexes with GRIP and AMPARs [39], making them potential phosphatases involved in synaptic plasticity. Indeed, LAR-RPTPs could be the target of the broad spectrum PTP inhibitors that we have shown block mAChR-LTD. In contrast, since mGluR-LTD does not involve liprin-α, it is likely that it utilises a different PTP, such as STEP [71]. Conversely, NMDAR-LTD does not seem to involve PTPs of any kind, rather it involves serine/threonine protein phosphatases [31] and protein tyrosine kinases (PTKs) [72, 73]. What is most clear from the present results is that there is a specific mechanism that is engaged for the regulation of synaptic AMPARs by the stimulation of muscarinic receptors, which is distinct from that employed by the activation of glutamate receptors. This might relate to the differences in the location of the glutamate receptors and muscarinic receptors that are activated by their respective neurotransmitters.

Significance of the findings for cognition

The critical involvement of ACh in cognition is well established. It is likely that the ability of muscarinic receptor activation to modulate NMDAR-dependent synaptic plasticity and to induce synaptic plasticity in an NMDAR-independent manner are both important aspects of this function. Dissecting the relative roles of the cholinergic modulation of NMDAR-dependent synaptic plasticity and the cholinergic induction of LTD will be important challenges for the future. Interestingly, mGluR-LTD and mAChR-LTD are likely to be evoked under quite different conditions. The former requires strong activation of glutamatergic pathways and constitutes a form of homosynaptic plasticity. In contrast, mAChR-LTD can be induced with little or no activation of the glutamatergic system, and hence constitutes a form of heterosynaptic plasticity. In this way, cholinergic activation could simultaneously boost both NMDAR-dependent synaptic plasticity at strongly active inputs and depress transmission at inactive, or weakly active, inputs.

Conclusion

We have identified a novel mechanism of synaptic plasticity that is specifically engaged during muscarinic receptor activation. This mechanism is not utilised by mGluR activation, demonstrating that different Gq-coupled receptors can affect AMPAR trafficking via distinct molecular mechanisms.

Methods

Electrophysiology

Hippocampal slices were obtained from 4–5 week old male Wistar rats. Animals were sacrificed by cervical dislocation in accordance with the UK Animals Scientific Procedures Act of 1986. The brains were quickly removed and transferred into ice-cold artificial cerebrospinal fluid (aCSF; bubbled with 95% O2/5% CO2) containing the following: (mM) NaCl, 124; KCl, 3; NaHCO3, 26; NaH2PO4, 1.25; CaCl2, 2; MgSO4, 1; D glucose, 10. Subsequently, a mid-sagittal cut was made in the brain and one hemisphere was placed back into the ice cold aCSF until it was required. Transverse hippocampal slices (400 μm) were prepared using either a vibratome (Leica, Nussloch, Germany) or a McIllwain tissue chopper (Mickle Laboratory Engineering Co. Ltd., Gomshall, UK). The slices were then submerged in aCSF (20°C–25°C) for at least 1 hour before recording. Slices were then transferred to the recording chamber and perfused with aCSF (28°C–30°C, flow rate 2~3 ml/min). Before recording, the CA3 region of the hippocampus was severed using a scalpel cut.
Whole-cell recordings were made from pyramidal cells in the CA1 region of the hippocampus (Axopatch 200 B amplifier, Molecular Devices, Sunnyvale, California). The patch pipette (resistance – 4–7 MΩ), pulled from borosilicate glass, was filled with a solution composed of (mM) CsMeSO4, 130; NaCl, 8; Mg-ATP, 4; Na-GTP, 0.3; EGTA, 0.5; HEPES 10; QX-314, 6 (280 mOsm [pH 7.2]). CA1 pyramidal neurons were voltage clamped at -70 mV and AMPA receptor-mediated synaptic currents were measured in the presence of picrotoxin (20 μM). Stimulating electrodes placed into the Schaffer collateral-commissural pathway, in the CA2 region, delivered stimuli at a frequency of 0.033 Hz. Series resistance and input resistance were monitored during the experiment and experimental data was not included if changes > 10% were seen.
In all experiments a baseline of at least 10 minutes was obtained before application of CCh or 77-LH-28-1. After drug application a washout period of 30–40 minutes was obtained. In experiments where pep2-SVKI, pep2-SVKE, pep2-EVKI, TVRTYSC and TVRTASC were incorporated into the pipette filling solution (Figure 3 and 4) a 20–30 minute baseline was obtained to ensure effective loading of the peptide and for stabilization of any effects on baseline transmission. The peptides, pep2-SVKI, pep2-SVKE and pep2-EVKI were purchased from Tocris (Bristol, UK) while TVRTYSC and TVRTASC were purchased from Peptide Protein Research LTD (Fareham, Hampshire, UK). BAPTA, cyclopiazonic acid, Ro 32-0432, PKC19-31, okadaic acid, cyclosporin A, anisomycin, cycloheximide, orthovanadate, phenylarsine oxide and GDPβS were added to the whole cell-patch filling solution. These chemicals were purchased from Calbiochem (California, U.S.A.). Picrotoxin, pirenzepine, and LY367385 were purchased from Tocris (Bristol, UK). Carbachol was purchased from SigmaAldrich (St Louis, U.S.A.). MPEP and D-AP5 was purchased from Ascent Scientific (Bristol, UK). These chemicals were made up as a stock solution and diluted to their final appropriate concentration in aCSF as required (indicated in Figures).

Biotinylation

Surface expression of GluA2 was analysed with a commercial surface labelling kit according to the manufacturer's instructions (Thermo Fisher Scientific Inc., Rockford, IL, USA). Briefly, 400 μm thick hippocampal slices (6 slices for each lane) were incubated with aCSF containing 1 mg/ml sulfosuccinimidyl-6-(biotinamido) hexanoate for 45 min on ice, quenched by further incubation in aCSF containing 100 mM glycine, and followed by two washes in ice-cold Tris-buffered saline (50 mM Tris, pH 7.5, 150 mM NaCl). Crude cell lysates were prepared in modified RIPA buffer containing 50 mM Tris (pH 7.6), 150 mM NaCl, 0.5% Triton X-100, 0.5% sodium deoxycholate, 0.1% SDS, 5 mM NaF, 1 mM Na3VO4 and protease inhibitor cocktail (SigmaAldrich, St Louis, U.S.A.). Small aliquots of each lysates were kept for total GluA2 protein levels. The detergent-solubilized lysates were incubated with 50 μl of hydrated Neutravidin-Agarose beads for 4 h at 4°C to isolate biotinylated proteins. After the Neutravidin beads were washed four times with the RIPA buffer, bound proteins were eluted with SDS sample buffer by boiling for 5 min. Isolated biotinylated proteins and whole cell lysates were subsequently analyzed by western blotting with monoclonal anti-GluA2 (1:1,000; 556341, BD Bioscience, Frankin Lakes, NJ, USA). Immunoreactive bands were then probed with HRP-conjugated secondary antibody for 1 h and developed using the ECL detection system (Thermo Fisher Scientific Inc.). Equal loading of isolated surface proteins was confirmed based on silver-stained bands profiles on gels that were pre-run with small aliquots of samples. Optical densities of immunoreactivities were quantified using NIH ImageJ software (downloaded from http://​rsb.​info.​nih.​gov/​ij/​).

Data Analysis

A sophisticated, free data acquisition and analysis package, the "LTP program" [74], was used to record the data, which had been filtered at 2 kHz and digitized at 10 kHz. During whole cell patch recording excitatory postsynaptic current (EPSC) amplitude, series resistance, DC current and input resistance were recorded. To graphically display the data, the amplitude of the EPSCs was normalized against baseline values and plotted against time. In the figures each data point represents the average of two raw data points. In each figure, data are shown as mean ± SEM. Where appropriate, the statistical significance of the data was established through use of a Student's t test, which was performed on EPSC amplitude measurements obtained during the 5 minutes before and between 25 and 30 minutes following washout of the muscarinic agonist.

Acknowledgements

This work was supported by the BBSRC (KC), UK Alzheimer Research Trust (KC, GLC) and the MRC (KC, GLC). GLC is a Wolfson-Royal Society fellow.
Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://​creativecommons.​org/​licenses/​by/​2.​0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

BAD conducted electrophysiology. JJ participated in the electrophysiology experiments. HS designed and participated in molecular experiments. GHS conducted molecular experiments. DJW participated in electrophysiology. CHD participated production of the M1 agonist. MS, GLC and KC conceived the original concept of this study and wrote the manuscript. KC supervised the entire project. All authors read and approved the final manuscript.

Unsere Produktempfehlungen

e.Med Interdisziplinär

Kombi-Abonnement

Für Ihren Erfolg in Klinik und Praxis - Die beste Hilfe in Ihrem Arbeitsalltag

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de.

e.Med Neurologie & Psychiatrie

Kombi-Abonnement

Mit e.Med Neurologie & Psychiatrie erhalten Sie Zugang zu CME-Fortbildungen der Fachgebiete, den Premium-Inhalten der dazugehörigen Fachzeitschriften, inklusive einer gedruckten Zeitschrift Ihrer Wahl.

e.Med Neurologie

Kombi-Abonnement

Mit e.Med Neurologie erhalten Sie Zugang zu CME-Fortbildungen des Fachgebietes, den Premium-Inhalten der neurologischen Fachzeitschriften, inklusive einer gedruckten Neurologie-Zeitschrift Ihrer Wahl.

Literatur
1.
Zurück zum Zitat Bartus RT, Dean RL, Beer B, Lippa AS: The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982, 217: 408-414. 10.1126/science.7046051.CrossRefPubMed Bartus RT, Dean RL, Beer B, Lippa AS: The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982, 217: 408-414. 10.1126/science.7046051.CrossRefPubMed
2.
Zurück zum Zitat Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR: Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982, 215: 1237-1239. 10.1126/science.7058341.CrossRefPubMed Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR: Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982, 215: 1237-1239. 10.1126/science.7058341.CrossRefPubMed
3.
Zurück zum Zitat Woolf NJ: A structural basis for memory storage in mammals. Prog Neurobiol. 1998, 55: 59-77. 10.1016/S0301-0082(97)00094-4.CrossRefPubMed Woolf NJ: A structural basis for memory storage in mammals. Prog Neurobiol. 1998, 55: 59-77. 10.1016/S0301-0082(97)00094-4.CrossRefPubMed
4.
Zurück zum Zitat Gold PE: Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol Learn Mem. 2003, 80: 194-210. 10.1016/j.nlm.2003.07.003.CrossRefPubMed Gold PE: Acetylcholine modulation of neural systems involved in learning and memory. Neurobiol Learn Mem. 2003, 80: 194-210. 10.1016/j.nlm.2003.07.003.CrossRefPubMed
5.
Zurück zum Zitat Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR: Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol. 1981, 10: 122-126. 10.1002/ana.410100203.CrossRefPubMed Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR: Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol. 1981, 10: 122-126. 10.1002/ana.410100203.CrossRefPubMed
6.
Zurück zum Zitat Arendt T, Bigl V, Arendt A, Tennstedt A: Loss of neurons in the nucleus basalis of Meynert in Alzheimer's disease, paralysis agitans and Korsakoff's Disease. Acta Neuropathol (Berl). 1983, 61: 101-108. 10.1007/BF00697388.CrossRef Arendt T, Bigl V, Arendt A, Tennstedt A: Loss of neurons in the nucleus basalis of Meynert in Alzheimer's disease, paralysis agitans and Korsakoff's Disease. Acta Neuropathol (Berl). 1983, 61: 101-108. 10.1007/BF00697388.CrossRef
7.
Zurück zum Zitat DeKosky ST, Scheff SW: Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990, 27: 457-464. 10.1002/ana.410270502.CrossRefPubMed DeKosky ST, Scheff SW: Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990, 27: 457-464. 10.1002/ana.410270502.CrossRefPubMed
8.
Zurück zum Zitat Levey AI: Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease. Proc Natl Acad Sci USA. 1996, 93: 13541-13546. 10.1073/pnas.93.24.13541.PubMedCentralCrossRefPubMed Levey AI: Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease. Proc Natl Acad Sci USA. 1996, 93: 13541-13546. 10.1073/pnas.93.24.13541.PubMedCentralCrossRefPubMed
9.
Zurück zum Zitat Forlenza OV, Spink JM, Dayanandan R, Anderton BH, Olesen OF, Lovestone S: Muscarinic agonists reduce tau phosphorylation in non neuronal cells via GSK-3beta inhibition and in neurons. J Neural Transm. 2000, 107: 1201-1212. 10.1007/s007020070034.CrossRefPubMed Forlenza OV, Spink JM, Dayanandan R, Anderton BH, Olesen OF, Lovestone S: Muscarinic agonists reduce tau phosphorylation in non neuronal cells via GSK-3beta inhibition and in neurons. J Neural Transm. 2000, 107: 1201-1212. 10.1007/s007020070034.CrossRefPubMed
10.
Zurück zum Zitat Beach TG, Walker DG, Potter PE, Sue LI, Fisher A: Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists. Brain Res. 2001, 905: 220-223. 10.1016/S0006-8993(01)02484-2.CrossRefPubMed Beach TG, Walker DG, Potter PE, Sue LI, Fisher A: Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists. Brain Res. 2001, 905: 220-223. 10.1016/S0006-8993(01)02484-2.CrossRefPubMed
11.
Zurück zum Zitat Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, LaFerla FM: M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron. 2006, 49: 671-682. 10.1016/j.neuron.2006.01.020.CrossRefPubMed Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, LaFerla FM: M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron. 2006, 49: 671-682. 10.1016/j.neuron.2006.01.020.CrossRefPubMed
12.
Zurück zum Zitat Langmead CJ, Watson J, Reavill C: Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Therapeutic. 2008, 117: 232-244. 10.1016/j.pharmthera.2007.09.009.CrossRef Langmead CJ, Watson J, Reavill C: Muscarinic acetylcholine receptors as CNS drug targets. Pharmacol Therapeutic. 2008, 117: 232-244. 10.1016/j.pharmthera.2007.09.009.CrossRef
13.
Zurück zum Zitat Kirkwood A, Rozas C, Kirkwood J, Perez F, Bear MF: Modulation of long-term synaptic depression in visual cortex by acetylcholine and norepinephrine. J Neurosci. 1999, 19: 1599-1609.PubMed Kirkwood A, Rozas C, Kirkwood J, Perez F, Bear MF: Modulation of long-term synaptic depression in visual cortex by acetylcholine and norepinephrine. J Neurosci. 1999, 19: 1599-1609.PubMed
14.
Zurück zum Zitat McCoy PA, McMahon LL: Muscarinic receptor dependent long-term depression in rat visual cortex is PKC independent but requires ERK1/2 activation and protein synthesis. J Neurophysiol. 2007, 98: 1862-1870. 10.1152/jn.00510.2007.CrossRefPubMed McCoy PA, McMahon LL: Muscarinic receptor dependent long-term depression in rat visual cortex is PKC independent but requires ERK1/2 activation and protein synthesis. J Neurophysiol. 2007, 98: 1862-1870. 10.1152/jn.00510.2007.CrossRefPubMed
15.
Zurück zum Zitat McCoy P, Norton TT, McMahon LL: Layer 2/3 synapses in monocular and binocular regions of tree shrew visual cortex express mAChR-dependent long-term depression and long-term potentiation. J Neurophysiol. 2008, 100: 336-345. 10.1152/jn.01134.2007.PubMedCentralCrossRefPubMed McCoy P, Norton TT, McMahon LL: Layer 2/3 synapses in monocular and binocular regions of tree shrew visual cortex express mAChR-dependent long-term depression and long-term potentiation. J Neurophysiol. 2008, 100: 336-345. 10.1152/jn.01134.2007.PubMedCentralCrossRefPubMed
16.
Zurück zum Zitat Massey PV, Bhabra G, Cho K, Brown MW, Bashir ZI: Activation of muscarinic receptors induces protein synthesis-dependent long-lasting depression in the perirhinal cortex. Eur J Neurosci. 2001, 14: 145-152. 10.1046/j.0953-816x.2001.01631.x.CrossRefPubMed Massey PV, Bhabra G, Cho K, Brown MW, Bashir ZI: Activation of muscarinic receptors induces protein synthesis-dependent long-lasting depression in the perirhinal cortex. Eur J Neurosci. 2001, 14: 145-152. 10.1046/j.0953-816x.2001.01631.x.CrossRefPubMed
17.
Zurück zum Zitat Jo J, Ball SM, Seok H, Oh SB, Massey PV, Molnar E, Bashir ZI, Cho K: Experience-dependent modification of mechanisms of long-term depression. Nat Neurosci. 2006, 9: 170-172. 10.1038/nn1637.CrossRefPubMed Jo J, Ball SM, Seok H, Oh SB, Massey PV, Molnar E, Bashir ZI, Cho K: Experience-dependent modification of mechanisms of long-term depression. Nat Neurosci. 2006, 9: 170-172. 10.1038/nn1637.CrossRefPubMed
18.
Zurück zum Zitat Grishin AA, Benquet P, Gerber U: Muscarinic receptor stimulation reduces NMDA responses in CA3 hippocampal pyramidal cells via Ca2+-dependent activation of tyrosine phosphatase. Neuropharmacology. 2005, 49: 328-337. 10.1016/j.neuropharm.2005.03.019.CrossRefPubMed Grishin AA, Benquet P, Gerber U: Muscarinic receptor stimulation reduces NMDA responses in CA3 hippocampal pyramidal cells via Ca2+-dependent activation of tyrosine phosphatase. Neuropharmacology. 2005, 49: 328-337. 10.1016/j.neuropharm.2005.03.019.CrossRefPubMed
19.
Zurück zum Zitat Scheiderer CL, McCutchen E, Thacker EE, Kolasa K, Ward MK, Parsons D, Harrell LE, Dobrunz LE, McMahon LL: Sympathetic sprouting drives hippocampal cholinergic reinnervation that prevents loss of a muscarinic receptor-dependent long-term depression at CA3-CA1 synapses. J Neurosci. 2006, 26: 3745-3756. 10.1523/JNEUROSCI.5507-05.2006.CrossRefPubMed Scheiderer CL, McCutchen E, Thacker EE, Kolasa K, Ward MK, Parsons D, Harrell LE, Dobrunz LE, McMahon LL: Sympathetic sprouting drives hippocampal cholinergic reinnervation that prevents loss of a muscarinic receptor-dependent long-term depression at CA3-CA1 synapses. J Neurosci. 2006, 26: 3745-3756. 10.1523/JNEUROSCI.5507-05.2006.CrossRefPubMed
20.
Zurück zum Zitat Volk LJ, Pfeiffer BE, Gibson JR, Huber KM: Multiple Gq-coupled receptors converge on a common protein synthesis-dependent long-term depression that is affected in fragile X syndrome mental retardation. J Neurosci. 2007, 27: 11624-11634. 10.1523/JNEUROSCI.2266-07.2007.CrossRefPubMed Volk LJ, Pfeiffer BE, Gibson JR, Huber KM: Multiple Gq-coupled receptors converge on a common protein synthesis-dependent long-term depression that is affected in fragile X syndrome mental retardation. J Neurosci. 2007, 27: 11624-11634. 10.1523/JNEUROSCI.2266-07.2007.CrossRefPubMed
21.
Zurück zum Zitat Scheiderer CL, Smith CC, McCutchen E, McCoy PA, Thacker EE, Kolasa K, Dobrunz LE, McMahon LL: Coactivation of M(1) muscarinic and alpha1 adrenergic receptors stimulates extracellular signal-regulated protein kinase and induces long-term depression at CA3-CA1 synapses in rat hippocampus. J Neurosci. 2008, 28: 5350-5358. 10.1523/JNEUROSCI.5058-06.2008.PubMedCentralCrossRefPubMed Scheiderer CL, Smith CC, McCutchen E, McCoy PA, Thacker EE, Kolasa K, Dobrunz LE, McMahon LL: Coactivation of M(1) muscarinic and alpha1 adrenergic receptors stimulates extracellular signal-regulated protein kinase and induces long-term depression at CA3-CA1 synapses in rat hippocampus. J Neurosci. 2008, 28: 5350-5358. 10.1523/JNEUROSCI.5058-06.2008.PubMedCentralCrossRefPubMed
22.
Zurück zum Zitat Moult PR, Gladding CM, Sanderson TM, Fitzjohn SM, Bashir ZI, Molnar E, Collingridge GL: Tyrosine phosphatases regulate AMPA receptor trafficking during metabotropic glutamate receptor-mediated long-term depression. J Neurosci. 2006, 26: 2544-2554. 10.1523/JNEUROSCI.4322-05.2006.CrossRefPubMed Moult PR, Gladding CM, Sanderson TM, Fitzjohn SM, Bashir ZI, Molnar E, Collingridge GL: Tyrosine phosphatases regulate AMPA receptor trafficking during metabotropic glutamate receptor-mediated long-term depression. J Neurosci. 2006, 26: 2544-2554. 10.1523/JNEUROSCI.4322-05.2006.CrossRefPubMed
23.
Zurück zum Zitat Moult PR, Correa SA, Collingridge GL, Fitzjohn SM, Bashir ZI: Co-activation of p38 mitogen-activated protein kinase and protein tyrosine phosphatase underlies metabotropic glutamate receptor-dependent long-term depression. J Physiol. 2008, 586: 2499-2510. 10.1113/jphysiol.2008.153122.PubMedCentralCrossRefPubMed Moult PR, Correa SA, Collingridge GL, Fitzjohn SM, Bashir ZI: Co-activation of p38 mitogen-activated protein kinase and protein tyrosine phosphatase underlies metabotropic glutamate receptor-dependent long-term depression. J Physiol. 2008, 586: 2499-2510. 10.1113/jphysiol.2008.153122.PubMedCentralCrossRefPubMed
24.
Zurück zum Zitat Collingridge GL, Olsen RW, Peters J, Spedding M: A nomenclature for ligand-gated ion channels. Neuropharmacology. 2009, 56: 2-5. 10.1016/j.neuropharm.2008.06.063.PubMedCentralCrossRefPubMed Collingridge GL, Olsen RW, Peters J, Spedding M: A nomenclature for ligand-gated ion channels. Neuropharmacology. 2009, 56: 2-5. 10.1016/j.neuropharm.2008.06.063.PubMedCentralCrossRefPubMed
25.
Zurück zum Zitat Lechleiter J, Hellmiss R, Duerson K, Ennulat D, David N, Clapham D, Peralta E: Distinct sequence elements control the specificity of G protein activation by muscarinic acetylcholine receptor subtypes. EMBO J. 1990, 9: 4381-4390.PubMedCentralPubMed Lechleiter J, Hellmiss R, Duerson K, Ennulat D, David N, Clapham D, Peralta E: Distinct sequence elements control the specificity of G protein activation by muscarinic acetylcholine receptor subtypes. EMBO J. 1990, 9: 4381-4390.PubMedCentralPubMed
26.
Zurück zum Zitat Lechleiter J, Girard S, Clapham D, Peralta E: Subcellular patterns of calcium release determined by G protein-specific residues of muscarinic receptors. Nature. 1991, 350: 505-508. 10.1038/350505a0.CrossRefPubMed Lechleiter J, Girard S, Clapham D, Peralta E: Subcellular patterns of calcium release determined by G protein-specific residues of muscarinic receptors. Nature. 1991, 350: 505-508. 10.1038/350505a0.CrossRefPubMed
27.
Zurück zum Zitat Berstein G, Blank JL, Smrcka AV, Higashijima T, Sternweis PC, Exton JH, Ross EM: Reconstitution of agonist-stimulated phosphatidylinositol 4,5-bisphosphate hydrolysis using purified m1 muscarinic receptor, Gq/11, and phospholipase C-beta 1. J Biol Chem. 1992, 267: 8081-8088.PubMed Berstein G, Blank JL, Smrcka AV, Higashijima T, Sternweis PC, Exton JH, Ross EM: Reconstitution of agonist-stimulated phosphatidylinositol 4,5-bisphosphate hydrolysis using purified m1 muscarinic receptor, Gq/11, and phospholipase C-beta 1. J Biol Chem. 1992, 267: 8081-8088.PubMed
28.
Zurück zum Zitat Felder CC: Muscarinic acetylcholine receptors: signal transduction through multiple effectors. FASEB J. 1995, 9: 619-625.PubMed Felder CC: Muscarinic acetylcholine receptors: signal transduction through multiple effectors. FASEB J. 1995, 9: 619-625.PubMed
29.
Zurück zum Zitat Artola A, Singer W: Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Trends Neurosci. 1993, 16: 480-487. 10.1016/0166-2236(93)90081-V.CrossRefPubMed Artola A, Singer W: Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Trends Neurosci. 1993, 16: 480-487. 10.1016/0166-2236(93)90081-V.CrossRefPubMed
30.
Zurück zum Zitat Mulkey RM, Herron CE, Malenka RC: An essential role for protein phosphatases in hippocampal long-term depression. Science. 1993, 261: 1051-1055. 10.1126/science.8394601.CrossRefPubMed Mulkey RM, Herron CE, Malenka RC: An essential role for protein phosphatases in hippocampal long-term depression. Science. 1993, 261: 1051-1055. 10.1126/science.8394601.CrossRefPubMed
31.
Zurück zum Zitat Mulkey RM, Endo S, Shenolikar S, Malenka RC: Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature. 1994, 369: 486-488. 10.1038/369486a0.CrossRefPubMed Mulkey RM, Endo S, Shenolikar S, Malenka RC: Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature. 1994, 369: 486-488. 10.1038/369486a0.CrossRefPubMed
32.
Zurück zum Zitat Watabe AM, Carlisle HJ, O'Dell TJ: Postsynaptic induction and presynaptic expression of group 1 mGluR-dependent LTD in the hippocampal CA1 region. J Neurophysiol. 2002, 87 (3): 1395-1403.PubMed Watabe AM, Carlisle HJ, O'Dell TJ: Postsynaptic induction and presynaptic expression of group 1 mGluR-dependent LTD in the hippocampal CA1 region. J Neurophysiol. 2002, 87 (3): 1395-1403.PubMed
33.
Zurück zum Zitat Lefkowitz RJ, Shenoy SK: Transduction of receptor signals by b-arrestins. Science. 2005, 308: 512-517. 10.1126/science.1109237.CrossRefPubMed Lefkowitz RJ, Shenoy SK: Transduction of receptor signals by b-arrestins. Science. 2005, 308: 512-517. 10.1126/science.1109237.CrossRefPubMed
34.
Zurück zum Zitat Li P, Kerchner GA, Sala C, Wei F, Huettner JE, Sheng M, Zhuo M: AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses. Nat Neurosci. 1999, 2: 972-977. 10.1038/14771.CrossRefPubMed Li P, Kerchner GA, Sala C, Wei F, Huettner JE, Sheng M, Zhuo M: AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses. Nat Neurosci. 1999, 2: 972-977. 10.1038/14771.CrossRefPubMed
35.
Zurück zum Zitat Daw MI, Chittajallu R, Bortolotto ZA, Dev KK, Duprat F, Henley JM, Collingridge GL, Isaac JT: PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses. Neuron. 2000, 28: 873-886. 10.1016/S0896-6273(00)00160-4.CrossRefPubMed Daw MI, Chittajallu R, Bortolotto ZA, Dev KK, Duprat F, Henley JM, Collingridge GL, Isaac JT: PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses. Neuron. 2000, 28: 873-886. 10.1016/S0896-6273(00)00160-4.CrossRefPubMed
36.
Zurück zum Zitat Bellone C, Luscher C: Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat Neurosci. 2006, 9: 636-641. 10.1038/nn1682.CrossRefPubMed Bellone C, Luscher C: Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat Neurosci. 2006, 9: 636-641. 10.1038/nn1682.CrossRefPubMed
37.
Zurück zum Zitat Xia J, Chung HJ, Wihler C, Huganir RL, Linden DJ: Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron. 2000, 28: 499-510. 10.1016/S0896-6273(00)00128-8.CrossRefPubMed Xia J, Chung HJ, Wihler C, Huganir RL, Linden DJ: Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron. 2000, 28: 499-510. 10.1016/S0896-6273(00)00128-8.CrossRefPubMed
38.
Zurück zum Zitat Wyszynski M, Kim E, Dunah AW, Passafaro M, Valtschanoff JG, Serra-Pages C, Streuli M, Weinberg RJ, Sheng M: Interaction between GRIP and liprin-alpha/SYD2 is required for AMPA receptor targeting. Neuron. 2002, 34: 39-52. 10.1016/S0896-6273(02)00640-2.CrossRefPubMed Wyszynski M, Kim E, Dunah AW, Passafaro M, Valtschanoff JG, Serra-Pages C, Streuli M, Weinberg RJ, Sheng M: Interaction between GRIP and liprin-alpha/SYD2 is required for AMPA receptor targeting. Neuron. 2002, 34: 39-52. 10.1016/S0896-6273(02)00640-2.CrossRefPubMed
39.
Zurück zum Zitat Dunah AW, Hueske E, Wyszynski M, Hoogenraad CC, Jaworski J, Pak DT, Simonetta A, Liu G, Sheng M: LAR receptor protein tyrosine phosphatases in the development and maintenance of excitatory synapses. Nat Neurosci. 2005, 8: 458-467.PubMed Dunah AW, Hueske E, Wyszynski M, Hoogenraad CC, Jaworski J, Pak DT, Simonetta A, Liu G, Sheng M: LAR receptor protein tyrosine phosphatases in the development and maintenance of excitatory synapses. Nat Neurosci. 2005, 8: 458-467.PubMed
40.
Zurück zum Zitat Johnson KG, McKinnell IW, Stoker AW, Holt CE: Receptor protein tyrosine phosphatases regulate retinal ganglion cell axon outgrowth in the developing Xenopus visual system. J Neurobiol. 2001, 49: 99-117. 10.1002/neu.1068.CrossRefPubMed Johnson KG, McKinnell IW, Stoker AW, Holt CE: Receptor protein tyrosine phosphatases regulate retinal ganglion cell axon outgrowth in the developing Xenopus visual system. J Neurobiol. 2001, 49: 99-117. 10.1002/neu.1068.CrossRefPubMed
41.
Zurück zum Zitat Van Lieshout EM, Van der Heijden I, Hendriks WJ, Van der Zee CE: A decrease in size and number of basal forebrain cholinergic neurons is paralleled by diminished hippocampal cholinergic innervation in mice lacking leukocyte common antigen-related protein tyrosine phosphatase activity. Neuroscience. 2001, 102: 833-841. 10.1016/S0306-4522(00)00526-1.CrossRefPubMed Van Lieshout EM, Van der Heijden I, Hendriks WJ, Van der Zee CE: A decrease in size and number of basal forebrain cholinergic neurons is paralleled by diminished hippocampal cholinergic innervation in mice lacking leukocyte common antigen-related protein tyrosine phosphatase activity. Neuroscience. 2001, 102: 833-841. 10.1016/S0306-4522(00)00526-1.CrossRefPubMed
42.
Zurück zum Zitat McCutchen E, Scheiderer CL, Dobrunz LE, McMahon LL: Coexistence of muscarinic long-term depression with electrically induced long-term potentiation and depression at CA3-CA1 synapses. J Neurophysiol. 2006, 96: 3114-3121. 10.1152/jn.00144.2006.CrossRefPubMed McCutchen E, Scheiderer CL, Dobrunz LE, McMahon LL: Coexistence of muscarinic long-term depression with electrically induced long-term potentiation and depression at CA3-CA1 synapses. J Neurophysiol. 2006, 96: 3114-3121. 10.1152/jn.00144.2006.CrossRefPubMed
43.
Zurück zum Zitat Choi SY, Chang J, Jiang B, Seol GH, Min SS, Han JS, Shin HS, Gallagher M, Kirkwood A: Multiple receptors coupled to phospholipase C gate long-term depression in visual cortex. J Neurosci. 2005, 25: 11433-11443. 10.1523/JNEUROSCI.4084-05.2005.CrossRefPubMed Choi SY, Chang J, Jiang B, Seol GH, Min SS, Han JS, Shin HS, Gallagher M, Kirkwood A: Multiple receptors coupled to phospholipase C gate long-term depression in visual cortex. J Neurosci. 2005, 25: 11433-11443. 10.1523/JNEUROSCI.4084-05.2005.CrossRefPubMed
44.
Zurück zum Zitat Markram H, Segal M: Acetylcholine potentiates responses to N-methyl-D-aspartate in the rat hippocampus. Neurosci Lett. 1990, 113: 62-65. 10.1016/0304-3940(90)90495-U.CrossRefPubMed Markram H, Segal M: Acetylcholine potentiates responses to N-methyl-D-aspartate in the rat hippocampus. Neurosci Lett. 1990, 113: 62-65. 10.1016/0304-3940(90)90495-U.CrossRefPubMed
45.
Zurück zum Zitat Harvey J, Balasubramaniam R, Collingridge GL: Carbachol can potentiate N-methyl-D-aspartate responses in the rat hippocampus by a staurosporine and thapsigargin-insensitive mechanism. Neurosci Lett. 1993, 162: 165-168. 10.1016/0304-3940(93)90586-A.CrossRefPubMed Harvey J, Balasubramaniam R, Collingridge GL: Carbachol can potentiate N-methyl-D-aspartate responses in the rat hippocampus by a staurosporine and thapsigargin-insensitive mechanism. Neurosci Lett. 1993, 162: 165-168. 10.1016/0304-3940(93)90586-A.CrossRefPubMed
46.
Zurück zum Zitat Marino MJ, Rouse ST, Levey AI, Potter LT, Conn PJ: Activation of the genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells. Proc Natl Acad Sci USA. 1998, 95: 11465-11470. 10.1073/pnas.95.19.11465.PubMedCentralCrossRefPubMed Marino MJ, Rouse ST, Levey AI, Potter LT, Conn PJ: Activation of the genetically defined m1 muscarinic receptor potentiates N-methyl-D-aspartate (NMDA) receptor currents in hippocampal pyramidal cells. Proc Natl Acad Sci USA. 1998, 95: 11465-11470. 10.1073/pnas.95.19.11465.PubMedCentralCrossRefPubMed
47.
Zurück zum Zitat Palmer MJ, Irving AJ, Seabrook GR, Jane DE, Collingridge GL: The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus. Neuropharmacology. 1997, 36: 1517-1532. 10.1016/S0028-3908(97)00181-0.CrossRefPubMed Palmer MJ, Irving AJ, Seabrook GR, Jane DE, Collingridge GL: The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus. Neuropharmacology. 1997, 36: 1517-1532. 10.1016/S0028-3908(97)00181-0.CrossRefPubMed
48.
Zurück zum Zitat Fitzjohn SM, Kingston AE, Lodge D, Collingridge GL: DHPG-induced LTD in area CA1 of juvenile rat hippocampus; characterisation and sensitivity to novel mGlu receptor antagonists. Neuropharmacology. 1999, 38: 1577-1583. 10.1016/S0028-3908(99)00123-9.CrossRefPubMed Fitzjohn SM, Kingston AE, Lodge D, Collingridge GL: DHPG-induced LTD in area CA1 of juvenile rat hippocampus; characterisation and sensitivity to novel mGlu receptor antagonists. Neuropharmacology. 1999, 38: 1577-1583. 10.1016/S0028-3908(99)00123-9.CrossRefPubMed
49.
Zurück zum Zitat Huber KM, Roder JC, Bear MF: Chemical induction of mGluR5- and protein synthesis-dependent long-term depression in hippocampal area CA1. J Neurophysiol. 2001, 86: 321-325.PubMed Huber KM, Roder JC, Bear MF: Chemical induction of mGluR5- and protein synthesis-dependent long-term depression in hippocampal area CA1. J Neurophysiol. 2001, 86: 321-325.PubMed
50.
Zurück zum Zitat Faas GC, Adwanikar H, Gereau RW 4th, Saggau P: Modulation of presynaptic calcium transients by metabotropic glutamate receptor activation: a differential role in acute depression of synaptic transmission and long-term depression. J Neurosci. 2002, 22: 6885-6890.PubMed Faas GC, Adwanikar H, Gereau RW 4th, Saggau P: Modulation of presynaptic calcium transients by metabotropic glutamate receptor activation: a differential role in acute depression of synaptic transmission and long-term depression. J Neurosci. 2002, 22: 6885-6890.PubMed
51.
Zurück zum Zitat Hou L, Klann E: Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci. 2004, 24: 6352-6361. 10.1523/JNEUROSCI.0995-04.2004.CrossRefPubMed Hou L, Klann E: Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci. 2004, 24: 6352-6361. 10.1523/JNEUROSCI.0995-04.2004.CrossRefPubMed
52.
Zurück zum Zitat Huang CC, You JL, Wu MY, Hsu KS: Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J Biol Chem. 2004, 279: 12286-12292. 10.1074/jbc.M312868200.CrossRefPubMed Huang CC, You JL, Wu MY, Hsu KS: Rap1-induced p38 mitogen-activated protein kinase activation facilitates AMPA receptor trafficking via the GDI.Rab5 complex. Potential role in (S)-3,5-dihydroxyphenylglycene-induced long term depression. J Biol Chem. 2004, 279: 12286-12292. 10.1074/jbc.M312868200.CrossRefPubMed
53.
Zurück zum Zitat Scheiderer CL, Dobrunz LE, McMahon LL: Novel form of long-term synaptic depression in rat hippocampus induced by activation of alpha 1 adrenergic receptors. J Neurophysiol. 2004, 91: 1071-1077. 10.1152/jn.00420.2003.CrossRefPubMed Scheiderer CL, Dobrunz LE, McMahon LL: Novel form of long-term synaptic depression in rat hippocampus induced by activation of alpha 1 adrenergic receptors. J Neurophysiol. 2004, 91: 1071-1077. 10.1152/jn.00420.2003.CrossRefPubMed
54.
Zurück zum Zitat Jo J, Heon S, Kim MJ, Son GH, Park Y, Henley JM, Weiss JL, Sheng M, Collingridge GL, Cho K: Metabotropic glutamate receptor-mediated LTD involves two interacting Ca2+ sensors, NCS-1 and PICK1. Neuron. 2008, 60: 1095-1111. 10.1016/j.neuron.2008.10.050.PubMedCentralCrossRefPubMed Jo J, Heon S, Kim MJ, Son GH, Park Y, Henley JM, Weiss JL, Sheng M, Collingridge GL, Cho K: Metabotropic glutamate receptor-mediated LTD involves two interacting Ca2+ sensors, NCS-1 and PICK1. Neuron. 2008, 60: 1095-1111. 10.1016/j.neuron.2008.10.050.PubMedCentralCrossRefPubMed
55.
Zurück zum Zitat Schnabel R, Kilpatrick IC, Collingridge GL: An investigation into signal transduction mechanisms involved in DHPG-induced LTD in the CA1 region of the hippocampus. Neuropharmacology. 1999, 38: 1585-1596. 10.1016/S0028-3908(99)00062-3.CrossRefPubMed Schnabel R, Kilpatrick IC, Collingridge GL: An investigation into signal transduction mechanisms involved in DHPG-induced LTD in the CA1 region of the hippocampus. Neuropharmacology. 1999, 38: 1585-1596. 10.1016/S0028-3908(99)00062-3.CrossRefPubMed
56.
Zurück zum Zitat Schnabel R, Kilpatrick IC, Collingridge GL: Protein phosphatase inhibitors facilitate DHPG-induced LTD in the CA1 region of the hippocampus. Br J Pharmacol. 2001, 132: 1095-1101. 10.1038/sj.bjp.0703905.PubMedCentralCrossRefPubMed Schnabel R, Kilpatrick IC, Collingridge GL: Protein phosphatase inhibitors facilitate DHPG-induced LTD in the CA1 region of the hippocampus. Br J Pharmacol. 2001, 132: 1095-1101. 10.1038/sj.bjp.0703905.PubMedCentralCrossRefPubMed
57.
Zurück zum Zitat Fitzjohn SM, Palmer MJ, May JER, Neeson A, Morris SAC, Collingridge GL: A characterisation of long-term depression induced by metabotropic glutamate receptor activation in the rat hippocampus in vitro. J Physiol. 2001, 537: 421-430. 10.1111/j.1469-7793.2001.00421.x.PubMedCentralCrossRefPubMed Fitzjohn SM, Palmer MJ, May JER, Neeson A, Morris SAC, Collingridge GL: A characterisation of long-term depression induced by metabotropic glutamate receptor activation in the rat hippocampus in vitro. J Physiol. 2001, 537: 421-430. 10.1111/j.1469-7793.2001.00421.x.PubMedCentralCrossRefPubMed
58.
Zurück zum Zitat Collingridge GL, Isaac JT, Wang YT: Receptor trafficking and synaptic plasticity. Nat Rev Neurosci. 2004, 5: 952-962. 10.1038/nrn1556.CrossRefPubMed Collingridge GL, Isaac JT, Wang YT: Receptor trafficking and synaptic plasticity. Nat Rev Neurosci. 2004, 5: 952-962. 10.1038/nrn1556.CrossRefPubMed
59.
Zurück zum Zitat Osten P, Khatri L, Perez JL, Kohr G, Giese G, Daly C, Schulz TW, Wensky A, Lee LM, Ziff EB: Mutagenesis reveals a role for ABP/GRIP binding to GluR2 in synaptic surface accumulation of the AMPA receptor. Neuron. 2000, 27: 313-325. 10.1016/S0896-6273(00)00039-8.CrossRefPubMed Osten P, Khatri L, Perez JL, Kohr G, Giese G, Daly C, Schulz TW, Wensky A, Lee LM, Ziff EB: Mutagenesis reveals a role for ABP/GRIP binding to GluR2 in synaptic surface accumulation of the AMPA receptor. Neuron. 2000, 27: 313-325. 10.1016/S0896-6273(00)00039-8.CrossRefPubMed
60.
Zurück zum Zitat Perez JL, Khatri L, Chang C, Srivastava S, Osten P, Ziff EB: PICK1 Targets Activated Protein Kinase C{alpha} to AMPA Receptor Clusters in Spines of Hippocampal Neurons and Reduces Surface Levels of the AMPA-Type Glutamate Receptor Subunit 2. J Neurosci. 2001, 21: 5417-5428.PubMed Perez JL, Khatri L, Chang C, Srivastava S, Osten P, Ziff EB: PICK1 Targets Activated Protein Kinase C{alpha} to AMPA Receptor Clusters in Spines of Hippocampal Neurons and Reduces Surface Levels of the AMPA-Type Glutamate Receptor Subunit 2. J Neurosci. 2001, 21: 5417-5428.PubMed
61.
Zurück zum Zitat Seidenman KJ, Steinberg JP, Huganir R, Malinow R: Glutamate receptor subunit 2 Serine 880 phosphorylation modulates synaptic transmission and mediates plasticity in CA1 pyramidal cells. J Neurosci. 2003, 23: 9220-9228.PubMed Seidenman KJ, Steinberg JP, Huganir R, Malinow R: Glutamate receptor subunit 2 Serine 880 phosphorylation modulates synaptic transmission and mediates plasticity in CA1 pyramidal cells. J Neurosci. 2003, 23: 9220-9228.PubMed
62.
Zurück zum Zitat Lu W, Ziff EB: PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking. Neuron. 2005, 47: 407-421. 10.1016/j.neuron.2005.07.006.CrossRefPubMed Lu W, Ziff EB: PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking. Neuron. 2005, 47: 407-421. 10.1016/j.neuron.2005.07.006.CrossRefPubMed
63.
Zurück zum Zitat Chung HJ, Steinberg JP, Huganir RL, Linden DJ: Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science. 2003, 300: 1751-1755. 10.1126/science.1082915.CrossRefPubMed Chung HJ, Steinberg JP, Huganir RL, Linden DJ: Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science. 2003, 300: 1751-1755. 10.1126/science.1082915.CrossRefPubMed
64.
Zurück zum Zitat Steinberg JP, Takamiya K, Shen Y, Xia J, Rubio ME, Yu S, Jin W, Thomas GM, Linden DJ, Huganir RL: Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression. Neuron. 2006, 49: 845-860. 10.1016/j.neuron.2006.02.025.CrossRefPubMed Steinberg JP, Takamiya K, Shen Y, Xia J, Rubio ME, Yu S, Jin W, Thomas GM, Linden DJ, Huganir RL: Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression. Neuron. 2006, 49: 845-860. 10.1016/j.neuron.2006.02.025.CrossRefPubMed
65.
Zurück zum Zitat Mameli M, Balland B, Lujan R, Luscher C: Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science. 2007, 317: 530-533. 10.1126/science.1142365.CrossRefPubMed Mameli M, Balland B, Lujan R, Luscher C: Rapid synthesis and synaptic insertion of GluR2 for mGluR-LTD in the ventral tegmental area. Science. 2007, 317: 530-533. 10.1126/science.1142365.CrossRefPubMed
66.
Zurück zum Zitat Dong H, O'Brien RJ, Fung ET, Lanhan AA, Worley PF, Huganir RL: GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature. 1997, 386: 279-284. 10.1038/386279a0.CrossRefPubMed Dong H, O'Brien RJ, Fung ET, Lanhan AA, Worley PF, Huganir RL: GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature. 1997, 386: 279-284. 10.1038/386279a0.CrossRefPubMed
67.
Zurück zum Zitat Liu SJ, Cull-Candy SG: Subunit interaction with PICK and GRIP controls Ca2+ permeability of AMPARs at cerebellar synapses. Nat Neurosci. 2005, 8: 768-775. 10.1038/nn1468.CrossRefPubMed Liu SJ, Cull-Candy SG: Subunit interaction with PICK and GRIP controls Ca2+ permeability of AMPARs at cerebellar synapses. Nat Neurosci. 2005, 8: 768-775. 10.1038/nn1468.CrossRefPubMed
68.
Zurück zum Zitat DeSouza S, Fu J, States BA, Ziff EB: Differential palmitoylation directs the AMPA receptor-binding protein ABP to spines or to intracellular clusters. J Neurosci. 2002, 22: 3493-3503.PubMed DeSouza S, Fu J, States BA, Ziff EB: Differential palmitoylation directs the AMPA receptor-binding protein ABP to spines or to intracellular clusters. J Neurosci. 2002, 22: 3493-3503.PubMed
69.
Zurück zum Zitat Dong H, Zhang P, Song I, Petralia RS, Liao D, Huganir RL: Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2. J Neurosci. 1999, 19: 6930-6941.PubMed Dong H, Zhang P, Song I, Petralia RS, Liao D, Huganir RL: Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2. J Neurosci. 1999, 19: 6930-6941.PubMed
70.
Zurück zum Zitat Ye B, Liao D, Zhang X, Zhang P, Dong H, Huganir RL: GRASP-1: a neuronal RasGEF associated with the AMPA receptor/GRIP complex. Neuron. 2000, 26: 603-617. 10.1016/S0896-6273(00)81198-8.CrossRefPubMed Ye B, Liao D, Zhang X, Zhang P, Dong H, Huganir RL: GRASP-1: a neuronal RasGEF associated with the AMPA receptor/GRIP complex. Neuron. 2000, 26: 603-617. 10.1016/S0896-6273(00)81198-8.CrossRefPubMed
71.
Zurück zum Zitat Zhang Y, Venkitaramani DV, Gladding CM, Zhang Y, Kurup P, Molnar E, Collingridge GL, Lombroso PJ: The tyrosine phosphatase STEP mediates AMPA receptor endocytosis after metabotropic glutamate receptor stimulation. J Neurosci. 2008, 28: 10561-10566. 10.1523/JNEUROSCI.2666-08.2008.PubMedCentralCrossRefPubMed Zhang Y, Venkitaramani DV, Gladding CM, Zhang Y, Kurup P, Molnar E, Collingridge GL, Lombroso PJ: The tyrosine phosphatase STEP mediates AMPA receptor endocytosis after metabotropic glutamate receptor stimulation. J Neurosci. 2008, 28: 10561-10566. 10.1523/JNEUROSCI.2666-08.2008.PubMedCentralCrossRefPubMed
72.
Zurück zum Zitat Ahmadian G, Ju W, Liu L, Wyszynski M, Lee SH, Dunah AW, Taghibiglou C, Wang Y, Lu J, Wong TP: Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD. EMBO J. 2004, 23: 1040-1050. 10.1038/sj.emboj.7600126.PubMedCentralCrossRefPubMed Ahmadian G, Ju W, Liu L, Wyszynski M, Lee SH, Dunah AW, Taghibiglou C, Wang Y, Lu J, Wong TP: Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD. EMBO J. 2004, 23: 1040-1050. 10.1038/sj.emboj.7600126.PubMedCentralCrossRefPubMed
73.
Zurück zum Zitat Hayashi T, Huganir RL: Tyrosine phosphorylation and regulation of the AMPA receptor by Src family tyrosine kinases. J Neurosci. 2004, 24: 6152-6160. 10.1523/JNEUROSCI.0799-04.2004.CrossRefPubMed Hayashi T, Huganir RL: Tyrosine phosphorylation and regulation of the AMPA receptor by Src family tyrosine kinases. J Neurosci. 2004, 24: 6152-6160. 10.1523/JNEUROSCI.0799-04.2004.CrossRefPubMed
74.
Zurück zum Zitat Anderson WW, Collingridge GL: The LTP Program: a data acquisition program for on-line analysis of long-term potentiation and other synaptic events. J Neurosci Methods. 2001, 108: 71-83. 10.1016/S0165-0270(01)00374-0.CrossRefPubMed Anderson WW, Collingridge GL: The LTP Program: a data acquisition program for on-line analysis of long-term potentiation and other synaptic events. J Neurosci Methods. 2001, 108: 71-83. 10.1016/S0165-0270(01)00374-0.CrossRefPubMed
Metadaten
Titel
A novel mechanism of hippocampal LTD involving muscarinic receptor-triggered interactions between AMPARs, GRIP and liprin-α
verfasst von
Bryony A Dickinson
Jihoon Jo
Heon Seok
Gi Hoon Son
Daniel J Whitcomb
Ceri H Davies
Morgan Sheng
Graham L Collingridge
Kwangwook Cho
Publikationsdatum
01.12.2009
Verlag
BioMed Central
Erschienen in
Molecular Brain / Ausgabe 1/2009
Elektronische ISSN: 1756-6606
DOI
https://doi.org/10.1186/1756-6606-2-18

Weitere Artikel der Ausgabe 1/2009

Molecular Brain 1/2009 Zur Ausgabe

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Thrombektomie auch bei großen Infarkten von Vorteil

16.05.2024 Ischämischer Schlaganfall Nachrichten

Auch ein sehr ausgedehnter ischämischer Schlaganfall scheint an sich kein Grund zu sein, von einer mechanischen Thrombektomie abzusehen. Dafür spricht die LASTE-Studie, an der Patienten und Patientinnen mit einem ASPECTS von maximal 5 beteiligt waren.

Schwindelursache: Massagepistole lässt Otholiten tanzen

14.05.2024 Benigner Lagerungsschwindel Nachrichten

Wenn jüngere Menschen über ständig rezidivierenden Lagerungsschwindel klagen, könnte eine Massagepistole der Auslöser sein. In JAMA Otolaryngology warnt ein Team vor der Anwendung hochpotenter Geräte im Bereich des Nackens.

Schützt Olivenöl vor dem Tod durch Demenz?

10.05.2024 Morbus Alzheimer Nachrichten

Konsumieren Menschen täglich 7 Gramm Olivenöl, ist ihr Risiko, an einer Demenz zu sterben, um mehr als ein Viertel reduziert – und dies weitgehend unabhängig von ihrer sonstigen Ernährung. Dafür sprechen Auswertungen zweier großer US-Studien.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.