Differential regulation of neurotrophin expression in basal forebrain astrocytes by neuronal signals

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3) promote the function and/or survival of basal forebrain (BF) cholinergic neurons in vivo and in culture. The neurotrophin source is commonly thought to be targets of cholinergic neurons and the possibility that local glial sources support cholinergic neurons has not been well examined. These sources, however, may be critical to BF neurons before or even after they reach their targets. We investigated neurotrophin expression in BF astrocytes and its regulation by neural signals. Solution hybridization and immunocytochemical assays revealed that NGF, BDNF, and NT(3) mRNA and proteins were expressed in cultured BF astrocytes. To investigate roles of neuronal signals in neurotrophin regulation, effects of K(+), glutamate, and the cholinergic agonist carbachol were examined. These stimuli affected neurotrophin expression differentially. KCl increased BDNF mRNA but did not alter NGF or NT(3) mRNA. The effect was blocked by nifedipine, suggesting that it was mediated by L-type voltage-dependent calcium currents. Carbachol also increased BDNF mRNA levels without changing NGF or NT(3). Effects were blocked by the muscarinic antagonist, atropine. In contrast, glutamate increased both NGF and BDNF mRNA. NT(3) mRNA again was unaffected. The metabotropic agonist trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) reproduced glutamate effects, whereas kainate or N-methyl-D-aspartate (NMDA) plus glycine did not. Lack of antagonism by ionotropic antagonists and blockade of glutamate effects by metabotropic antagonists confirmed metabotropic mediation. We suggest that BF astrocytes are local sources of neurotrophins for BF cholinergic neurons during development and are regulated differentially by specific neuronal signals. Critical neuronal-glial interactions may underlie basal forebrain function.