Altered hippocampal circuit function in C3H α7 null mutant heterozygous mice

Abstract

The α7 subtype of nicotinic receptor is highly expressed in the hippocampus where it is purported to modulate release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). The α7 receptormediated release of GABA is thought to contribute to hippocampal inhibition (gating) of response to repetitive auditory stimulation. This hypothesis is supported by observations of hippocampal auditory gating deficits in mouse strains with low levels of hippocampal α7 receptors compared to strains with high levels of hippocampal α7 receptors. The difficulty with comparisons between mouse strains, however, is that different strains have different genetic backgrounds. Thus, the observed interstrain differences in hippocampal auditory gating might result from factors other than interstrain variations in the density of hippocampal α7 receptors. To address this issue, hippocampal binding of the α7 receptor-selective antagonist α-bungarotoxin as well as hippocampal auditory gating characteristics were compared in C3H wild type and C3H α7 receptor null mutant heterozygous mice. The C3H α7 heterozygous mice exhibited significant reductions in hippocampal α7 receptors levels and abnormal hippocampal auditory gating compared to the C3H wild type mice. In addition, a general increase in CA3 pyramidal neuron responsivity was observed in the heterozygous mice compared to the wild type mice. These data suggest that decreasing hippocampal α7 receptor density results in a profound alteration in hippocampal circuit function.

Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

“…Of particular relevance to attentional and sensory gating deficits in schizophrenia (Adler et al, 1998;Heinrichs, 2005;Lubow, 2005), a7-nAChR agonists alleviate both types of deficits in humans and animals Olincy et al, 2006;Timmermann et al, 2007;Wishka et al, 2006). A role for the a7-nAChR in these processes is supported by findings that a7-nAChR knock-out mice show attentional and gating impairments (Adams et al, 2008;Hoyle et al, 2006;Young et al, 2004Young et al, , 2007. Finally, there is a diminished expression of a7-nAChR in the hippocampus and frontal cortex in schizophrenia (Freedman et al, 1995;Guan et al, 1999).…”

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…However, both of these studies only assessed male mice, therefore no sex comparisons have been made here. α7-nicotinic acetylcholine receptor knockout mice (α7-nAChR KO) show deficits in sensory inhibition, working memory and attention, as well as reduced cortical expression levels of parvalbumin and NMDAR at adulthood(Fernandes et al 2006;Young et al 2007;Adams et al 2008). From 10 original manuscripts assessing this model, seven included males only, and two reported no sex differences, although limited sample sizes were used(Young et al 2011;Stevens et al 2014).…”

The 15q13.3 deletion syndrome: Deficient α7-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders

“…From a functional perspective, diminished expression of α 7 nAChRs due to a heterozygous deletion of 15q13.3 encompassing CHRNA7 is associated with reduced inhibitory circuit function in the hippocampus (Adams et al 2008(Adams et al , 2012. The conservation of the human 15q13.3 genomic region in mice has led to the creation of heterozygous mouse models with good construct validity for the human deletion syndrome (Fejgin et al 2014); mouse chromosome 7 contains the orthologous genomic region.…”