Research articleMemantine, an NMDA receptor antagonist, improves working memory deficits in DGKβ knockout mice
Introduction
Diacylglycerol kinase (DGK) is a member of the lipid kinases, and it phosphorylates diacylglycerol (DG) into phosphatidic acid (PA) downstream of Gq protein–coupled receptor signaling [18], [31], [32], [33]. DG modulates not only protein kinase C function, but also other functional proteins such as Ras guanyl-releasing protein, protein kinase D, transient receptor potential cation channel C, and chimerins [18], [31], [32], [33]. PA also has functions as a signal mediator, regulating the mammalian target of rapamycin, phosphatidylinositol 4-phosphate 5-kinase, and Akt [18], [31], [32], [33]. Hence, DGK is a key second messenger that plays multiple roles in regulating cell signaling.
In mammals, 10 DGK isozymes have been identified so far [26], and recently the function of each isozyme has become clearer. Among DGK isozymes, DGKβ is classified as type 1, has EF-hand and recoverin homology, and shows Ca2+ sensitivity. DGKβ is widely distributed in the brain, especially in the olfactory bulb, cerebral cortex, striatum, and hippocampus [10]. We previously investigated the various roles of DGKβ in higher brain function, and found the following: (i) DGKβ is involved in neurite spine formation. DGKβ knock out (KO) mice showed significant reduction of spine density in the cortex, striatum, and hippocampus, which resulted in impairment of hippocampal long-term potentiation (LTP) and cognitive dysfunction [12], [17], [29]. (ii) DGKβ KO mice also showed hyper locomotion, reduced anxiety, and attention deficit behaviors [13], [17]. These behaviors indicate that DGKβ also has a key role in emotion. It has been reported that a splice variant at the COOH-terminal of DGKβ was related to bipolar disorder [5]. (iii) Finally, DGKβ influenced the sensitivity to seizure-inducing stimuli [15].
Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist [7]. In many countries, it has been approved for the treatment of moderate to severe Alzheimer's disease (AD). Memantine has relatively low affinity for the NMDA receptor, strong voltage dependency, fast kinetics, and inhibits only low firing responses to the NMDA receptor [7]. These characteristics of memantine may enable the filtering of only the abnormal synaptic noise of AD patients without affecting the physiological stimuli of the NMDA receptor [16]. Therefore, memantine is of clinical benefit to AD patients. In preclinical studies, memantine also improved cognitive function and had neuroprotective effects not only in an AD animal model, but also in many other animal models such as the aged rodent, psychiatric disease model, and pharmacologically induced dementia animal model [2], [4], [6], [8], [19], [20].
In the present study, to explore the characteristics of cognitive dysfunction in DGKβ KO mice and the involvement of NMDA receptor signaling in it, we evaluated the effects of memantine on the cognitive deficits in DGKβ KO mice and investigated the expression levels of NMDA receptor subunits in DGKβ KO mice.
Section snippets
Animals
DGKβ KO mice were generated using the Sleeping Beauty transposon system and backcrossed for more than nine generations onto a C57BL/N genetic background, as described previously [29]. In all experiments, we used littermates of DGKβ KO mice and wild-type (WT) mice generated by breeding heterozygous mutants. The animals (male, 10–48 weeks old) were housed at 24 ± 2 °C under a 12 h light-dark cycle (lights on from 08:00 to 20:00) and had ad libitum access to food and water. Behavioral experiments were
Memantine improved working memory deficit in DGKβ KO mice
We previously determined that DGKβ had an essential role in neurite spine formation, and demonstrated that DGKβ KO mice showed cognitive deficits in both behavioral and electrophysiological aspects [29]. The cognitive dysfunctions of DGKβ KO mice were ameliorated by administering a mood stabilizer, valproate [14]. However, there have been no data about how memory-improving drugs, like anti-Alzheimer's drugs, may affect cognition in DGKβ KO mice. Therefore, we evaluated the effect of memantine,
Discussion
Since the cloning of DGKβ in 1993 [10], the distribution, localization, and developmental expression of DGKβ in the central nervous system (CNS) have been elucidated [1], [10]. By generating and screening the phenotype of DGKβ KO mice, we have also progressively clarified the function of DGKβ in the CNS. In the present study, we found that acute administration of an NMDA receptor inhibitor, memantine, attenuated the working memory deficit in DGKβ KO mice. We also detected altered expression
References (35)
- et al.
Immunocytochemical localization of a neuron-specific diacylglycerol kinase beta and gamma in the developing rat brain
Brain Res. Mol. Brain Res.
(2005) - et al.
Molecular cloning and characterization of the human diacylglycerol kinase beta (DGKbeta) gene: alternative splicing generates DGKbeta isotypes with different properties
J. Biol. Chem.
(2002) - et al.
Memantine potentiates hippocampal theta oscillations at a therapeutic dose in anesthetized mice: a mechanistic link to its cognitive-enhancing properties
Neuropharmacology
(2012) - et al.
Involvement of diacylglycerol kinase beta in the spine formation at distal dendrites of striatal medium spiny neurons
Brain Res.
(2015) - et al.
The effects of valproate and olanzapine on the abnormal behavior of diacylglycerol kinase beta knockout mice
Pharmacol. Rep.
(2015) - et al.
The in vivo relevance of the varied channel-blocking properties of uncompetitive NMDA antagonists: tests on spinal neurones
Neuropharmacology
(2001) - et al.
Characterization of cognitive deficits in a transgenic mouse model of Alzheimer's disease and effects of donepezil and memantine
Eur. J. Pharmacol.
(2013) - et al.
Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist–a review of preclinical data
Neuropharmacology
(1999) - et al.
Possible antidepressant effects and mechanisms of memantine in behaviors and synaptic plasticity of a depression rat model
Neuroscience
(2011) - et al.
Diacylglycerol kinases: why so many of them?
Biochim. Biophys. Acta
(2007)