Rescuing prefrontal cAMP-CREB pathway reverses working memory deficits during withdrawal from prolonged alcohol exposure.
Both human and animal studies indicate that alcohol withdrawal following chronic alcohol consumption (CAC) impairs many of the cognitive functions which rely on the prefrontal cortex (PFC). A candidate signaling cascade contributing to memory deficits during alcohol withdrawal is the protein kinase A (PKA)/cAMP-responsive element binding (CREB) cascade, although the role of PKA/CREB cascade in behavioral and molecular changes during sustained withdrawal period remains largely unknown. We demonstrated that 1 week (1W) or 6 weeks (6W) withdrawal after 6-month CAC impairs working memory (WM) in a T-maze spontaneous alternation task and reduces phosphorylated CREB (pCREB) in the PFC but not the dorsal CA1 region (dCA1) of the hippocampus compared with CAC and water conditions. In contrast, both CAC-unimpaired and withdrawn-impaired mice exhibited decreased pCREB in dCA1 as well as reduced histone H4 acetylation in PFC and dCA1, compared with water controls. Next, we showed that enhancing CREB activity through rolipram administration prior to testing improved WM performance in withdrawn mice but impaired WM function in water mice. In addition, WM improvement correlates positively with increased pCREB level selectively in the PFC of withdrawn mice. Results further indicate that direct infusion of the PKA activator (Sp-cAMPS) into the PFC significantly improves or impairs, respectively, WM performance in withdrawn and water animals. In contrast, Sp-cAMPS had no effect on WM when infused into the dCA1. Collectively, these results provide strong support that dysregulation of PKA/CREB-dependent processes in prefrontal neurons is a critical molecular signature underlying cognitive decline during alcohol withdrawal.
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Nouvelle Université de Bordeaux, CNRS UMR 5287, Talence, France.|U-930 Inserm, Université François Rabelais, Parc Grandmont, Tours, France.
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Dominguez
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Nouvelle Université de Bordeaux, CNRS UMR 5287, Talence, France.
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Dagnas
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Nouvelle Université de Bordeaux, CNRS UMR 5287, Talence, France.
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Decorte
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Nouvelle Université de Bordeaux, CNRS UMR 5287, Talence, France.
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Vandesquille
U-930 Inserm, Université François Rabelais, Parc Grandmont, Tours, France.
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Belzung
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Nouvelle Université de Bordeaux, CNRS UMR 5287, Talence, France.
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Béracochéa
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, Nouvelle Université de Bordeaux, CNRS UMR 5287, Talence, France. nicole.mons@u-bordeaux1.fr.
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Mons
D000437:Alcoholism / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D003072:Cognition Disorders / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000503:physiopathology*; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology*
D017362:Cyclic AMP Response Element-Binding Protein; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
Alcoholism; Behavior; Hippocampus; Histone acetylation; PKA; Prefrontal cortex