Neurotrophins and Neurotrophin Receptors in Adult Brain Plasticity

265 Neurotrophic factors stimulate survival and growth of neurons during development and are involved in the regulation of neuronal survival, plasticity and regeneration in the adult nervous system. These growth factors offer an avenue to develop effective therapy for disorders associated with degeneration and neuron loss. Earlier studies showed that nerve growth factor (NGF) protects basal forebrain cholinergic neurons from lesion-induced degeneration and stimulates acetylcholine synthesis and release by surviving cholinergic neurons. Cell culture studies revealed that brain-derived neurotrophic factor (BDNF) promotes the developmental differentiation of both basal forebrain cholinergic and mesencephalic dopaminergic neurons. However, in adult rats, BDNF was less potent and less effective than NGF in protecting forebrain cholinergic cell bodies from axotomy-induced degeneration and, in contrast to NGF, failed to increase presynaptic cholinergic function in the hippocampus. BDNF also failed to protect dopaminergic neurons after axotomy in the adult High levels of BDNF mRNA are found in cholinergic target areas of the brain such as the hippocampus. Recent findings suggest that the expression of BDNF mRNA in the hippocampus is regulated by the cholinergic input. We compared the effects of partial and full fimbrial transections, which result in, respectively, partial and near-total cholinergic deafferentation on the expression of BDNF mRNA. Twenty one days following partial unilateral fimbrial transections there were significant decreases of BDNF mRNA expression throughout the hippocampal formation. The largest decreases were noted in pyramidal CA1 and CA3 layers and in the den-tate gyrus. The decreases amounted to 22-36% reductions compared to unlesioned control animals. BDNF mRNA levels were decreased to a greater extent (50-69%) following full unilateral fimbrial transections. Quantitative Northern blot analysis indicated that hippo-campal BDNF mRNA was decreased by 29% and 68%, 3 weeks after partial or full unilateral fimbrial transections, respectively. The extent of the reductions in BDNF mRNA levels correlated with reductions in acetylcholinesterase (ACHE) staining density and cholinergic terminal density determined by quantitative auto-radiographic analysis of [H]vesamicol binding sites. In addition, we found that chronic treatment with atropine (20 mg/kg for 14 days) decreased BDNF mRNA levels in the pyramidal CA1, CA2 and CA3 layers and in the dentate gyrus by 54%. In contrast, chronic treatment with nicotine (1.18 mg/kg for 14 days), a treatment known to desensitize nicotinic receptors, did not affect BDNF mRNA expression in the hippocampal formation. These findings provide evidence for cholinergic muscarinic regulation of BDNF mRNA expression in the adult rat hippocampal formation and …