Trophic Effects of Excitatory Amino Acids in the Developing Nervous System

Cerebellar granule cells in culture exhibit specific survival requirements (e.g. Thangnipon et al., 1983; Kingsbury et al., 1985; Gallo et al., 1987a). These include chronic depolarization, usually effected by increasing the K+ concentration of the medium above the physiological level (≥20 mM). The dependence on ‘high’ K+ develops within a narrow window of time between 2 and 4 days in vitro (DIV) (Gallo et al., 1987a). It was also observed that the effect of depolarization on cell survival is mediated through stimulated Ca2+ influx via voltage sensitive Ca2+ channels (VSCC). On the basis of these findings we have put forward the hypothesis that the effect of high K+ in vitro mimics the influence of the first innervation the immediately postmigratory granule cells receive from the mossy fibres (Balazs and Jo/rgensen, 1987; Gallo et al., 1987a). Many of these fibres are glutamatergic (Somogyi et al., 1986) and granule cells are endowed with glutamate (Glu) receptors including the N-methyl- D-aspartate (NMDA)-preferring subtype (Cull-Candy et al., 1988), which is known to be linked to an ion channel whose Ca2+ permeability, in comparison with the other Glu receptor subtypes, is high (Mayer and Westbrook, 1987). The hypothesis predicted therefore that the trophic influence of the mossy fibre innervation is mediated through Ca2+ influx via the NMDA receptor-ionophore complex.