Cholinergic regulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) but not neurotrophin-3 (NT-3) mRNA levels in the developing rat hippocampus

In previous experiments it has been demonstrated that the synthesis of BDNF (brain-derived neurotrophic factor) and NGF in neurons of the hippocampus is regulated by neuronal activity. The glutamate system is predominantly responsible for upregulation and the GABAergic system for downregulation both in vitro and in vivo (Zafra et al., 1990, 1991 ). The aim of the present study is to examine the extent to which the cholinergic system is also involved in the regulation of NGF and BDNF mRNA and whether the regulatory contribution of the cholinergic system changes during development. Partial transection of the fimbria fornix bundle in the second postnatal week resulted in a reduction of BDNF and NGF mRNA levels in the hippocampus, suggesting that septal cholinergic input is involved in the regulation of hippocampal BDNF and NGF mRNA levels. Because the fimbria fornix bundle also contains fibers other than cholinergic ones, we further evaluated the importance of the cholinergic influence by injecting pilocarpine, a muscarinic agonist. Pilocarpine markedly increased hippocampal BDNF and NGF mRNA levels in both early postnatal and adult rats. In situ hybridization experiments demonstrated that pilocarpine led to an increase in BDNF expression in the CA1-CA4 regions of the hippocampus and in the dentate gyrus. However, pilocarpine increased NGF mRNA only in those neurons of the dentate gyrus and CA1-CA4 regions that also expressed NGF mRNA in the controls. Thus, the pattern of BDNF and NGF mRNA expression following pilocarpine administration is different from that observed following injection of kainic acid (KA) in adult animals. Administration of KA during the first 2 postnatal weeks affected neither NGF nor BDNF mRNA levels, in spite of producing generalized seizures. In contrast to NGF and BDNF, neurotrophin-3 mRNA levels were not changed by pilocarpine administration. The pilocarpine-mediated increase in BDNF mRNA was inhibited not only by the mus-carinic antagonist scopolamine, but also by MK-801, a noncompetitive antagonist of NMDA receptors, suggesting an involvement of these receptors in BDNF regulation. Moreover, intraventricular injection of NMDA increased BDNF mRNA expression in the hippocampus of postnatal day 7 rats. Thus, during early postnatal development the activity-dependent regulation of neurotrophins is not mediated by KA but NMDA receptors, which are also influenced by the cholinergic system.