Cholinergic regulation of hippocampal brain-derived neurotrophic factor mRNA expression: Evidence from lesion and chronic cholinergic drug treatment studies

Abstract

Quantitative in situ hybridization and northern blot analysis techniques were used to determine the effects of removal of the cholinergic input on levels and topographical distribution of brain-derived neurotrophic factor mRNA in the hippocampus of adult rats. First, the effects of partial and full fimbrial transections, which result in partial and near-total cholinergic deafferentation respectively, were compared. Twenty-one days after partial unilateral fimbrial transections, there were significant decreases in brain-derived neurotrophic factor mRNA expression throughout the hippocampal formation. Decreased expression of brain-derived neurotrophic factor mRNA was evident in all areas of localization within the hippocampal formation. The decreases amounted to 22–36% reductions compared with unlesioned control animals. Brain-derived neurotrophic factor mRNA levels were decreased to a greater extent (50–69%) following full unilateral fimbrial transections. Quantitative northern blot analysis indicated that hippocampal BDNF mRNA was decreased by 29 and 68%, three weeks after partial or full unilateral fimbrial transections, respectively. The extent of the reductions in brain-derived neurotrophic factor mRNA levels correlated with reductions in acetylcholinesterase staining density and cholinergic terminal density determined by quantitative autoradiographic analysis of [ 3H]vesamicol binding sites. Second, we found that chronic treatment with atropine (20 mg/kg per day for 14 days) decreased (by 54%) brain-derived neurotrophic factor mRNA levels in all areas of localization within the hippocampus. In contrast, chronic treatment with nicotine (1.18 mg/kg per day for 14 days), a treatment known to desensitize nicotinic receptors, did not affect brain-derived neurotrophic factor mRNA expression in the hippocampal formation. The findings provide evidence for cholinergic muscarinic regulation of brain-derived neurotrophic factor mRNA expression in the adult rat hippocampal formation and they suggest the existence of a tonic stimulation of brain-derived neurotrophic factor synthesis by the cholinergic afferents.