title: Genetic knockout of the α7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation in a background strain-dependent manner.
abstract: Reduced α7 nicotinic acetylcholine receptor (nAChR) function is linked to impaired hippocampal-dependent sensory processing and learning and memory in schizophrenia. While knockout of the Chrna7 gene encoding the α7nAChR on a C57/Bl6 background results in changes in cognitive measures, prior studies found little impact on hippocampal synaptic plasticity in these mice. However, schizophrenia is a multi-genic disorder where complex interactions between specific genetic mutations and overall genetic background may play a prominent role in determining phenotypic penetrance. Thus, we compared the consequences of knocking out the α7nAChR on synaptic plasticity in C57/Bl6 and C3H mice, which differ in their basal α7nAChR expression levels. Homozygous α7 deletion in C3H mice, which normally express higher α7nAChR levels, resulted in impaired long-term potentiation (LTP) at hippocampal CA1 synapses, while C3H α7 heterozygous mice maintained robust LTP. In contrast, homozygous α7 deletion in C57 mice, which normally express lower α7nAChR levels, did not alter LTP, as had been previously reported for this strain. Thus, the threshold of Chrna7 expression required for LTP may be different in the two strains. Measurements of auditory gating, a hippocampal-dependent behavioral paradigm used to identify schizophrenia-associated sensory processing deficits, was abnormal in C3H α7 knockout mice confirming that auditory gating also requires α7nAChR expression. Our studies highlight the importance of genetic background on the regulation of synaptic plasticity and could be relevant for understanding genetic and cognitive heterogeneity in human studies of α7nAChR dysfunction in mental disorders.
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Electronic address: Ron.Freund@UCDenver.edu.
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Freund
authors.affiliation: Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Graw
authors.affiliation: Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Choo
authors.affiliation: Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Medical Research Service, Veterans Affairs Medical Center, Denver, CO, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Stevens
authors.affiliation: Department of Psychiatry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Medical Research Service, Veterans Affairs Medical Center, Denver, CO, USA.
authors.forename: Sherry
authors.initials: S
authors.lastname: Leonard
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Neuroscience Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dell'Acqua
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D017774:Long-Term Potentiation / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H / Q000235:genetics* / Q000502:physiology; D008810:Mice, Inbred C57BL / Q000235:genetics* / Q000502:physiology; D018345:Mice, Knockout; D055139:Sensory Gating / Q000235:genetics; D013045:Species Specificity; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: C579166:Chrna7 protein, mouse; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Genetics; Hippocampal slice; Long-term potentiation; Mouse; α7 nicotinic acetylcholine receptor