Promoter IV ‐ BDNF deficiency disturbs cholinergic gene expression of CHRNA 5, CHRM 2, and CHRM 5: effects of drug and environmental treatments

Brain‐derived neurotrophic factor ( BDNF ) promotes maturation of cholinergic neurons. However, how activity‐dependent BDNF expression affects specific cholinergic gene expression remains unclear. This study addressed this question by determining mRNA levels of 22 acetylcholine receptor subunits, the choline transporter ( CHT ), and the choline acetyltransferase (Ch AT ) in mice deficient in activity‐dependent BDNF via promoter IV ( KIV ) and control wild‐type mice. Quantitative RT ‐ PCR revealed significant reductions in nicotinic acetylcholine receptor alpha 5 ( CHRNA 5) in the frontal cortex and hippocampus and M5 muscarinic acetylcholine receptor ( CHRM 5) in the hippocampus, but significant increases in M2 muscarinic acetylcholine receptor ( CHRM 2) in the frontal cortex of KIV mice compared to wild‐type mice. Three‐week treatments with fluoxetine, phenelzine, duloxetine, imipramine, or an enriched environment treatment ( EET ) did not affect the altered expression of these genes except that EET increased CHRNA 5 levels only in KIV frontal cortex. EET also increased levels of CHRNA 7, CHT , and Ch AT , again only in the KIV frontal cortex. The imipramine treatment was most prominent among the four antidepressants; it up‐regulated hippocampal CHRM 2 and frontal cortex CHRM 5 in both genotypes, and frontal cortex CHRNA 7 only in KIV mice. To the best of our knowledge, this is the first evidence that BDNF deficiency disturbs expression of CHRNA 5, CHRM 2, and CHRM 5. Our results suggest that promoter IV ‐ BDNF deficiency – which occurs under chronic stress – causes cholinergic dysfunctions via these receptors. EET is effective on CHRNA 5, while its compensatory induction of other cholinergic genes or drugs targeting CHRNA 5, CHRM 2, and CHRM 5 may become an alternative strategy to reverse these BDNF ‐linked cholinergic dysfunctions.