Ontogenesis of central excitatory synaptic receptors

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We studied ontogenic changes of NMDA receptors (NMDAR) in cerebellar granule cells by using patch clamp techniques applied to thin slices of brain tissues. By applying NMDA from outside to granule cells in whole-cell recording mode, we found that external granule cells before migration already express NMDA receptors. The NMDA responses of external granule cells showed typical voltage-dependent Mg blockade reported for NMDARs. Single channel recordings of NMDAR currents in outside-out patches excised from external granule cells showed 50 pS main conductance and 40 pS subconductance states as commonly described for NMDARs. These NMDARs may contribute to cell migration by providing cells with pathways for Ca entry. It has been reported that NMDA antagonist can suppress granule cell migration. Functional NMDAR density judged from the amplitude of NMDA-induced whole-cell current was low in external granule cells compared with that in internal granule cells. The density of migrating granule cell was intermediate, indicating that the density of NMDAR increase as the cells migrate (Farrant et al., Nature 1994, in press).We also found that the NMDARs in internal granule cells undergo developmental changes. At the early postnatal period (< 2 weeks), NMDAR-induced single channel currents were predominantly 50/40 ps in conductances. As animals grow older, chances of observing the NMDAR channel currents of 30/20 pS increased. From molecular studies it has reported that the mRNAs encoding the NMDAR in cerebellar granule cells switches from II_B to II_C at around 3 weeks postnatally. The II_B/I NMDARs expressed in Xenopus oocytes from cRNAs had 50/40 pS, whereas the II_C/I NMDARs expressed similarly had 30/20 pS. We conclude that II_B/II_C switching occurs in native tissue, thereby changing the channel properties (Farrant et al., Nature 1994, in press).