Reduced CHRNA7 expression in C3H mice is associated with increases in hippocampal parvalbumin and glutamate decarboxylase-67 (GAD67) as well as altered levels of GABA(A) receptor subunits.
Decreased expression of CHRNA7, the gene encoding the α7(∗) subtype of nicotinic receptor, may contribute to the cognitive dysfunction observed in schizophrenia by disrupting the inhibitory/excitatory balance in the hippocampus. C3H mice with reduced Chrna7 expression have significant reductions in hippocampal α7(∗) receptor density, deficits in hippocampal auditory gating, increased hippocampal activity as well as significant decreases in hippocampal glutamate decarboxylase-65 (GAD65) and γ-aminobutyric acid-A (GABAA) receptor levels. The current study investigated whether altered Chrna7 expression is associated with changes in the levels of parvalbumin, GAD67 and/or GABAA receptor subunits in the hippocampus from male and female C3H Chrna7 wildtype, C3H Chrna7 heterozygous and C3H Chrna7 knockout (KO) mice using quantitative Western immunoblotting. Reduced Chrna7 expression was associated with significant increases in hippocampal parvalbumin and GAD67 and with complex alterations in GABAA receptor subunits. A decrease in α3 subunit protein was seen in both female C3H Chrna7 Het and KO mice while a decrease in α4 subunit protein was also detected in C3H Chrna7 KO mice with no sex difference. In contrast, an increase in δ subunit protein was observed in C3H Chrna7 Het mice while a decrease in this subunit was observed in C3H Chrna7 KO mice, with δ subunit protein levels being greater in males than in females. Finally, an increase in γ2 subunit protein was found in C3H Chrna7 KO mice with the levels of this subunit again being greater in males than in females. The increases in hippocampal parvalbumin and GAD67 observed in C3H Chrna7 mice are contrary to reports of reductions in these proteins in the postmortem hippocampus from schizophrenic individuals. We hypothesize that the disparate results may occur because of the influence of factors other than CHRNA7 that have been found to be abnormal in schizophrenia.
Medical Research, Veterans Affairs Medical Center, Denver, CO 80220, United States; Department of Psychiatry, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, United States; Department of Integrative Biology, University of Colorado Denver Downtown Denver Campus, Denver, CO 80217, United States.
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RC
Bates
Department of Integrative Biology, University of Colorado Denver Downtown Denver Campus, Denver, CO 80217, United States.
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BJ
Stith
Medical Research, Veterans Affairs Medical Center, Denver, CO 80220, United States; Department of Psychiatry, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, United States.
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KE
Stevens
Medical Research, Veterans Affairs Medical Center, Denver, CO 80220, United States; Department of Psychiatry, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, United States. Electronic address: cehelmke@gmail.com.
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CE
Adams
D000818:Animals; D015153:Blotting, Western; D005260:Female; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006624:Hippocampus / Q000503:physiopathology*; D008297:Male; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010320:Parvalbumins / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D012727:Sex Characteristics; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*
C579166:Chrna7 protein, mouse; C546258:Gabra3 protein, mouse; C583130:Gabrd protein, mouse; C546280:Gabrg2 protein, mouse; D010320:Parvalbumins; D011963:Receptors, GABA-A; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
Chrna7; GABA(A) receptors; glutamate decarboxylase 67 (GAD67); parvalbumin; schizophrenia; λ-aminobutyric acid (GABA)