title: Glutamate and nicotinic receptor interactions in working memory: importance for the cognitive impairment of schizophrenia.
abstract: This article reaches across disciplines to correlate results in molecular, cellular, behavioral, and clinical research to develop a more complete picture of how working memory (WM) functions. It identifies a new idea that deserves further investigation. NMDA glutamate receptors (NMDAR) are critical for memory function. NMDAR inhibition effectively reproduces principal manifestations of schizophrenia (SP), such as WM impairment and GABAergic deficit (mainly reduction of glutamic acid decarboxylase 67 (GAD67) and parvalbumin (PV) content). Nicotine and selective α7 nicotinic acetylcholine receptor (nAChR) agonists reduce WM impairments in patients with SP and reverse WM deficits in animals treated with NMDAR antagonists. The mechanism of this effect is unknown. Importantly, WM recovery occurs even before restoration of NMDAR blockade-induced molecular alterations, including reduced GAD67 in interneurons. Our insight into the cognitive-enhancing effect of α7 nAChR agonists, particularly in the animal models of SP, combines reviews of recent findings on glutamate and nicotinic receptor expression in the neuronal circuits involved in WM, the properties of these receptors, their implication in WM regulation, generation of rhythmic neuronal activity, resulting in a proposed hypothesis for further investigations. We suggest that (1) cortical/hippocampal interneurons, particularly PV positive, play a crucial role in WM and that impairment of these cells in SP could be behind the WM deficit; (2) activation of α7 nAChRs could restore calcium signaling and intrinsic properties of these interneurons, and associated with these events, computational capacity, gamma rhythmic activity, and WM would also be restored.
authors: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 104790, Durham, NC 27710, USA. timofeev@duke.edu
authors: O A
authors: OA
authors: Timofeeva
authors: E D
authors: ED
authors: Levin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism; D006801:Humans; D008570:Memory, Short-Term / Q000502:physiology*; D017470:Receptors, Glutamate / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012559:Schizophrenia / Q000150:complications / Q000378:metabolism*
chemical_list: D017470:Receptors, Glutamate; D011978:Receptors, Nicotinic