PromoterIV‐BDNFdeficiency disturbs cholinergic gene expression ofCHRNA5,CHRM2, andCHRM5: effects of drug and environmental treatments

AbstractBrain‐derived neurotrophic factor (BDNF) promotes maturation of cholinergic neurons. However, how activity‐dependentBDNFexpression affects specific cholinergic gene expression remains unclear. This study addressed this question by determiningmRNAlevels of 22 acetylcholine receptor subunits, the choline transporter (CHT), and the choline acetyltransferase (ChAT) in mice deficient in activity‐dependentBDNFvia promoterIV(KIV) and control wild‐type mice. QuantitativeRT‐PCRrevealed significant reductions in nicotinic acetylcholine receptor alpha 5 (CHRNA5) in the frontal cortex and hippocampus and M5 muscarinic acetylcholine receptor (CHRM5) in the hippocampus, but significant increases in M2 muscarinic acetylcholine receptor (CHRM2) in the frontal cortex ofKIVmice 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 thatEETincreasedCHRNA5 levels only inKIVfrontal cortex.EETalso increased levels ofCHRNA7,CHT, and ChAT, again only in theKIVfrontal cortex. The imipramine treatment was most prominent among the four antidepressants; it up‐regulated hippocampalCHRM2 and frontal cortexCHRM5 in both genotypes, and frontal cortexCHRNA7 only inKIVmice. To the best of our knowledge, this is the first evidence thatBDNFdeficiency disturbs expression ofCHRNA5,CHRM2, andCHRM5. Our results suggest that promoterIV‐BDNFdeficiency – which occurs under chronic stress – causes cholinergic dysfunctions via these receptors.EETis effective onCHRNA5, while its compensatory induction of other cholinergic genes or drugs targetingCHRNA5,CHRM2, andCHRM5 may become an alternative strategy to reverse theseBDNF‐linked cholinergic dysfunctions.image