The transcription factor calcium-response factor limits NMDA receptor-dependent transcription in the developing brain.

Neuronal activity sculpts brain development by inducing the transcription of genes such as brain-derived neurotrophic factor ( Bdnf) that modulate the function of synapses. Sensory experience is transduced into changes in gene transcription via the activation of calcium signaling pathways downstream of both L-type voltage-gated calcium channels (L- VGCCs) and NMDA-type glutamate receptors ( NMDARs). These signaling pathways converge on the regulation of transcription factors including calcium-response factor (Ca RF). Although Ca RF is dispensable for the transcriptional induction of Bdnf following the activation of L- VGCCs, here we show that the loss of Ca RF leads to enhanced NMDAR-dependent transcription of Bdnf as well as Arc. We identify the NMDAR subunit-encoding gene Grin3a as a regulatory target of Ca RF, and we show that expression of both Carf and Grin3a is depressed by the elevation of intracellular calcium, linking the function of this transcriptional regulatory pathway to neuronal activity. We find that light-dependent activation of Bdnf and Arc transcription is enhanced in the visual cortex of young Ca RF knockout mice, suggesting a role for Ca RF-dependent dampening of NMDAR-dependent transcription in the developing brain. Finally, we demonstrate that enhanced Bdnf expression in Ca RF-lacking neurons increases inhibitory synapse formation. Taken together, these data reveal a novel role for Ca RF as an upstream regulator of NMDAR-dependent gene transcription and synapse formation in the developing brain. [ABSTRACT FROM AUTHOR]