CHOLINERGIC REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND NERVE GROWTH-FACTOR (NGF) BUT NOT NEUROTROPHIN-3 (NT-3) MESSENGER-RNA 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 hi ppocampus is regulated by neuronal activity. The glutamate system is p redominantly 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 cho linergic system is also involved in the regulation of NGF and BDNF mRN A and whether the regulatory contribution of the cholinergic system ch anges during development. Partial transection of the fimbria fornix bu ndle 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 t han cholinergic ones, we further evaluated the importance of the choli nergic influence by injecting pilocarpine, a muscarinic agonist. Piloc arpine markedly increased hippocampal BDNF and NGF mRNA levels in both early postnatal and adult rats. In situ hybridization experiments dem onstrated that pilocarpine led to an increase in BDNF expression in th e 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 pilocarp ine 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 administra tion. The pilocarpine-mediated increase in BDNF mRNA was inhibited not only by the muscarinic antagonist scopolamine, but also by MK-801, a noncompetitive antagonist of NMDA receptors, suggesting an involvement of these receptors in BDNF regulation. Moreover, intraventricular inj ection of NMDA increased BDNF mRNA expression in the hippocampus of po stnatal day 7 rats. Thus, during early postnatal development the activ ity-dependent regulation of neurotrophins is not mediated by KA but NM DA receptors, which are also influenced by the cholinergic system.