Hippocampal gene expression profiling reveals the possible involvement of Homer1 and GABA(B) receptors in scopolamine-induced amnesia.
Scopolamine-treated rats are commonly used as a psychopharmacological model of memory dysfunction and have been extensively studied to establish the effectiveness of acetylcholinesterase inhibitors in the treatment of Alzheimer's disease. Scopolamine is a muscarinic acetylcholine receptor antagonist that induces memory deficits in young subjects similar to those occurring during aging. The amnesic effect of scopolamine is well established but the molecular and cellular mechanisms that sustain its neuropharmacological action are still unclear. The present genome wide study investigates hippocampal gene expression profiling in scopolamine-treated adult rats following stimulation in a spatial memory task. Using microarray and quantitative real-time RT-PCR approaches, we identified several genes previously known to be associated with memory processes (Homer1, GABA(B) receptor, early growth response 1, prodynorphin, VGF nerve growth factor inducible) and multiple novel candidate genes possibly involved in cognition (including calcium/calmodulin-dependent protein kinase kinase 2, dual specificity phosphatase 5 and 6, glycophorin C) that were altered following scopolamine treatment. Moreover, we found that stable over-expression of glutamatergic components Homer1a and 1c in the hippocampus of adult rats induced by recombinant adeno-associated virus vector abolished memory improvement produced by the GABA(B) receptor antagonist SGS742 in scopolamine-treated rats. Taken together, these results reveal novel genes and mechanisms involved in scopolamine-induced amnesia, and demonstrate the involvement of both GABA and glutamate neurotransmission in this animal model of cognitive dysfunctions.
Brouillette
Jonathan
J
Department of Neurology & Neurosurgery, Douglas Mental Health University Institute, McGill University, Montréal, Quebec, CanadaDepartment of Molecular Medicine and Pathology, University of Auckland, Auckland, New ZealandDepartment of Psychiatry, Douglas Mental Health University Institute, McGill University, Montréal, Quebec, Canada.
Young
Deborah
D
Department of Neurology & Neurosurgery, Douglas Mental Health University Institute, McGill University, Montréal, Quebec, CanadaDepartment of Molecular Medicine and Pathology, University of Auckland, Auckland, New ZealandDepartment of Psychiatry, Douglas Mental Health University Institute, McGill University, Montréal, Quebec, Canada.
During
Matthew J
MJ
Department of Neurology & Neurosurgery, Douglas Mental Health University Institute, McGill University, Montréal, Quebec, CanadaDepartment of Molecular Medicine and Pathology, University of Auckland, Auckland, New ZealandDepartment of Psychiatry, Douglas Mental Health University Institute, McGill University, Montréal, Quebec, Canada.
Quirion
Rémi
R
Department of Neurology & Neurosurgery, Douglas Mental Health University Institute, McGill University, Montréal, Quebec, CanadaDepartment of Molecular Medicine and Pathology, University of Auckland, Auckland, New ZealandDepartment of Psychiatry, Douglas Mental Health University Institute, McGill University, Montréal, Quebec, Canada.
D000647:Amnesia / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D018756:GABA Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000072233:Homer Scaffolding Proteins; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D018080:Receptors, GABA-B / Q000235:genetics*; D012601:Scopolamine / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects; D015854:Up-Regulation / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002352:Carrier Proteins; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D000072233:Homer Scaffolding Proteins; C000606624:Homer1 protein, rat; D018727:Muscarinic Antagonists; D018080:Receptors, GABA-B; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D012601:Scopolamine