MODULATION OF GAP-43 MESSENGER-RNA BY GABA AND GLUTAMATE IN CULTURED CEREBELLAR GRANULE CELLS

Expression of GAP-43 in the cerebellum and selected regions of the bra in has been shown to be developmentally regulated. Localization of GAP -43 mRNA within granule cells of the immature and mature rat cerebellu m has been demonstrated by in situ hybridization. Higher levels are de tected in the neonate compared to the adult, To determine if the cereb ellar neurotransmitters, GABA (gamma-amino-butyric acid) and glutamate are involved in the modulation of GAP-43 expression, cultured cerebel lar granule cells were exposed to these transmitters. Cultures were tr eated with glutamate, GABA, or the agonists/antagonists to their recep tors in serum-free media for 5-7 days. Analysis of the levels of GAP-4 3 mRNA by in situ hybridization indicated that a 7-day exposure to GAB A (25 and 50 mu M) significantly lowered levels of granule cell GAP-43 mRNA, Specific agonists to the GABA(A) (muscimol) and GABA(B) (baclof en) receptors produced a decrease similar to that observed for GABA. R esults from these studies also indicated that exposure to non-NMDA (CN QX) and NMDA (CPP, MK-801) glutamate receptor antagonists, and a metab otropic receptor glutamate agonist (ACPD), decreased the level of GAP- 43 mRNA. The involvement of GABA and glutamate in the modulation of GA P-43 expression was corroborated by Northern hybridization. These stud ies revealed that a 5-day exposure to GABA decreased the cellular cont ent of GAP-43 mRNA by 21% whereas exposure to glutamate resulted in a 37% increase. Findings from the studies reported here, using an in vit ro cerebellar granule cell model, suggest that levels of GAP-43 mRNA, in vivo, are modulated by input from both excitatory glutamatergic mos sy fibers and inhibitory GABAegic Golgi interneurons. Thus, modulation of GAP-43 mRNA by these neurotransmitters may influence granule cell maturation during development in the neonate and neuroplasticity in th e adult, possibly at the parallel fiber-Purkinje cell synapse. (C) 199 8 Elsevier Science B.V.