Synaptic activity-dependent developmental regulation of NMDA receptor subunit expression in cultured neocortical neurons

The biophysical properties of NMDA receptors are thought to be critical det erminants involved in the regulation of long-term synaptic plasticity durin g neocortical development. NMDA receptor channel properties are strongly de pendent on the subunit composition of heteromeric NMDA receptors. During ne ocortical development in vivo, the expression of the NMDA receptor 2A (NR2A ) subunit is up-regulated at the mRNA and protein level correlating with ch anges in the kinetic and pharmacological properties of functional NMDA rece ptors. To investigate the developmental regulation of NMDA receptor subunit expression, we studied NR2 mRNA expression in cultured neocortical neurons . With increasing time in culture, they showed a similar up-regulation of N R2A mRNA expression as described in vivo. As demonstrated by chronic blocka de of postsynaptic glutamate receptors in vitro, the regulation of NR2A mRN A was strongly dependent on synaptic activity. In contrast, NR2B mRNA expre ssion was not influenced by activity blockade, Moreover, as shown pharmacol ogically, the regulation of NR2A mRNA expression was mediated by postsynapt ic Ca2+ influx through both NMDA receptors and L-type Ca2+ channels. It is interesting that even relatively weak expression of NR2A mRNA was correlate d with clearly reduced sensitivity of NMDA receptor-mediated whole-cell cur rents against the NR2B subunit-specific antagonist ifenprodil. Developmenta l changes in the expression of NR1 mRNA splice variants were also strongly dependent on synaptic activity and thus might, in addition to regulation of NR2 subunit expression, contribute to developmental changes in the propert ies of functional NMDA receptors. In summary, our results demonstrate that synaptic activity is a key factor in the regulation of NMDA receptor subuni t expression during neocortical development.