Genetic knockout of the α7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation in a background strain-dependent manner

Reduced alpha 7 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 alpha 7nAChR on a C57/B16 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 alpha 7nAChR on synaptic plasticity in C57/B16 and C3H mice, which differ in their basal alpha 7nAChR expression levels. Homozygous alpha 7 deletion in C3H mice, which normally express higher alpha 7nAChR levels, resulted in impaired long-term potentiation (LTP) at hippocampal CA1 synapses, while OH alpha 7 heterozygous mice maintained robust LTP. In contrast, homozygous alpha 7 deletion in C57 mice, which normally express lower alpha 7nAChR 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 OH alpha 7 knockout mice confirming that auditory gating also requires alpha 7nAChR 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 alpha 7nAChR dysfunction in mental disorders. (C) 2016 Elsevier Ireland Ltd. All rights reserved.