Altered adrenergic receptor signaling following traumatic brain injury contributes to working memory dysfunction

doi:10.1016/j.neuroscience.2010.10.048

Neuroscience

Volume 172, 13 January 2011, Pages 293-302

https://doi.org/10.1016/j.neuroscience.2010.10.048 Get rights and content

Abstract

The prefrontal cortex is highly vulnerable to traumatic brain injury (TBI) and its structural and/or functional alterations as a result of TBI can give rise to persistent working memory (WM) dysfunction. Using a rodent model of TBI, we have described profound WM deficits following TBI that are associated with increases in prefrontal catecholamine (both dopamine and norepinephrine) content. In this study, we examined if enhanced norepinephrine signaling contributes to TBI-associated WM dysfunction. We demonstrate that administration of α1 adrenoceptor antagonists, but not α2A agonist, at 14 days post-injury significantly improved WM performance. mRNA analysis revealed increased levels of α1A, but not α1B or α1D, adrenoceptor in the medial prefrontal cortex (mPFC) of brain-injured rats. As α1A and 1B adrenoceptor promoters contain putative cAMP response element (CRE) sequences, we therefore examined if CRE-binding protein (CREB) actively engages these sequences in order to increase receptor gene transcription following TBI. Our results show that the phosphorylation of CREB is enhanced in the mPFC at time points during which increased α1A mRNA expression was observed. Chromatin immunoprecipitation (ChIP) assays using mPFC tissue from injured animals indicated increased phospho-CREB binding to the CRE sites of α1A, but not α1B, promoter compared to that observed in uninjured controls. To address the translatability of our findings, we tested the efficacy of the FDA-approved α1 antagonist Prazosin and observed that this drug improves WM in injured animals. Taken together, these studies suggest that enhanced CREB-mediated expression of α1 adrenoceptor contributes to TBI-associated WM dysfunction, and therapies aimed at reducing α1 signaling may be useful in the treatment of TBI-associated WM deficits in humans.

Research Highlights

▶ TBI increases α_1A, but not α_1B or α_1D, adrenoceptor mRNA levels in mPFC. ▶ TBI increases the phosphorylation of CREB predominantly in GABAergic interneurons. ▶ TBI enhances the recruitment of phospho-CREB to the α_1A promoter. ▶ Systemic administration of α₁ antagonists improves working memory in injured animals.

Section snippets

Materials

Phospho-CREB (Ser¹³³) and pan-specific CREB antibodies were obtained from Cell Signaling Technology (Danvers, MA, USA). Monoclonal anti-glutamic acid decarboxylase 67 (GAD67) and monoclonal anti-NeuN antibodies were obtained from Millipore (Billerica, MA, USA). The α₁ adrenoceptor antagonist prazosin (1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine hydrochloride), α1 adrenoceptor antagonist HEAT (2-{[b-(4-Hydroxyphenyl)ethyl]aminomethyl}-1-tetralone hydrochloride), and

α₁ antagonist improves spatial working memory (WM) in injured rats

To test if norepinephrine signaling contributes to TBI-associated WM deficits, the influences of the α₁ selective antagonist HEAT (0.1 mg/kg) and the α_2A selective agonist guanfacine (0.1 mg/kg) were examined on day 14 post-injury, a time point when WM deficits have been observed following cortical impact injury.

Prior to testing the influence of adrenergic receptor agonist/antagonist, injured animals were given a series of training trials on day 12 post-injury (Fig. 1a). Fig. 1b shows summary

Discussion

This study revealed four key findings: (1) TBI increases α_1A, but not α_1B or α_1D, adrenoceptor mRNA levels in mPFC; (2) TBI increases the phosphorylation of CREB on Ser¹³³ predominantly in GABAergic interneurons; (3) TBI enhances the recruitment of phospho-CREB to the α_1A promoter; and (4) systemic administration of α₁ antagonists improves WM performance in injured animals. Taken together, these findings support the clinical usefulness of α₁ receptors antagonists as a treatment for WM

Conclusion

Enhanced CREB-mediated expression of α1 adrenoceptor contributes to TBI associated WM dysfunction, and therapies aimed at reducing α1 signaling may be useful in the treatment of TBI-associated WM deficits.

Acknowledgments

The authors would like to thank Anthony Moore and John Redell for critical review of the manuscript. This work was supported by grants [NS052313, NS49160, MH072933] from National Institutes of Health.

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Cognitive, Behavioral, and Systems NeuroscienceAltered adrenergic receptor signaling following traumatic brain injury contributes to working memory dysfunction

Abstract

Research Highlights

Section snippets

Materials

α1 antagonist improves spatial working memory (WM) in injured rats

Discussion

Conclusion

Acknowledgments

Biol Psychiatry

J Mol Cell Cardiol

Biol Psychiatry

Pharmacol Biochem Behav

Neuropsychopharmacology

Gene

J Biol Chem

Behav Neural Biol

Brain Res

J Biol Chem

Eur J Pharmacol

Pharmacol Biochem Behav

J Biol Chem

J Biol Chem

Biol Psychiatry

Trends Neurosci

Neuroscience

Through the looking glass: differential noradenergic modulation of prefrontal cortical function

Neural Plast

Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates

Science

Excitatory actions of norepinephrine on multiple classes of hippocampal CA1 interneurons

J Neurosci

Methods for determining numbers of cells and synapses: a case for more uniform standards of review

J Comp Neurol

Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury

J Neurosci Res

Cognitive, Behavioral, and Systems Neuroscience
Altered adrenergic receptor signaling following traumatic brain injury contributes to working memory dysfunction

α₁ antagonist improves spatial working memory (WM) in injured rats