NMDA receptor stimulation selectively initiates GABA(A) receptor delta subunit mRNA expression in cultured rat...

Findings in vivo and in culture suggest that neuronal activity selectively regulates GABA(A) receptor delta subunit mRNA expression in cerebellar granule neurons. For example, the onset of delta subunit mRNA expression during postnatal maturation coincides with innervation. Furthermore, depolarizing conditions (25 mM KCl) in culture initiate and maintain increases in the delta subunit transcript level. We have now examined whether similar changes in delta subunit mRNA expression occur in cultured neurons after activation of glutamate receptors of the NMDA subtype, an event that mimics granule neuron depolarization by mossy fiber innervation in vivo. Our studies demonstrate that addition of 50 microM NMDA to cultured rat granule neurons maintained in defined, serum-free medium specifically initiates delta subunit transcript expression. Whereas the level of the delta subunit mRNA is increased fourfold by this treatment, levels of other GABA(A) receptor subunit transcripts are not significantly changed. The level of the delta subunit transcript is further increased when NMDA receptor activation is enhanced by maintaining neurons in a Mg2+-free medium to alleviate Mg2+ blockade of the receptor channel. The NMDA-induced elevation in delta subunit transcript expression involves activation of a Ca2+/calmodulin-dependent protein kinase pathway. These findings suggest that activation of an excitatory pathway may regulate the expression of an inhibitory receptor phenotype in cerebellar granule neurons in vivo.