GRANULE NEURON REGULATION OF PURKINJE-CELL DEVELOPMENT - STRIKING A BALANCE BETWEEN NEUROTROPHIN AND GLUTAMATE SIGNALING

Granule neurons, presynaptic afferents of Purkinje cells, are potent r egulators of Purkinje cell development. Purified Purkinje cells surviv e and differentiate poorly, whereas coculture with granule neurons enh ances their survival and dendritic development. Here we investigate th e role of neurotrophins in granule-Purkinje cell interactions. BDNF or NT-4 improves, but NT-3 or CNTF reduces, survival of isolated Purkinj e cells. When granule neurons are present, however, BDNF or NT-4 treat ment leads to Purkinje cell loss. This decrease is overcome by anti-BD NF or TrkB-lgG-blocking reagents or by CNQX, a non-NMDA glutamate rece ptor antagonist. Furthermore, BDNF increases the spine density on the surviving Purkinje cells. These results suggest that Purkinje cell sur vival and differentiation are context-dependent and require a balance between neurotrophin-and activity-dependent signaling.