HIPK2-mediated transcriptional control of NMDA receptor subunit expression regulates neuronal survival and cell death

NMDA ( N -methyl D -aspartate) receptors are critical for neuronal communication. Dysfunction in NMDA receptors has been implicated in neuropsychiatric diseases. While it is well-recognized that the composition of NMDA receptors undergoes a GluN2B-to-GluN2A switch in early postnatal life, the mechanism regulating this switch remains unclear. Using transcriptomic and functional analyses in brain tissues from male and female Hipk2 +/+ and Hipk2 -/- mice, we showed that the HIPK2-JNK-c-Jun pathway is important in suppressing the transcription of Grin2a and Grin2c , which encodes the GluN2A and GluN2C subunits of the NMDA receptors, respectively. Loss of HIPK2 leads to a significant decrease in JNK-c-Jun signaling, which in turn de-represses the transcription of Grin2a and Grin2c mRNA and up-regulates GluN2A and GluN2C protein levels. These changes result in a significant increase of GluN2A/GluN2B ratio in synapse and mitochondria, a persistent activation of the ERK-CREB pathway and the up-regulation of synaptic activity-regulated genes, which collectively contribute to the resistance of Hipk2 -/- neurons to cell death induced by mitochondrial toxins. SIGNIFICANCE STATEMENT We identify HIPK2-JNK-c-Jun signaling as a key mechanism that regulates the transcription of NMDA receptor subunits GluN2A and GluN2C in vivo. Our results provide insights into a previously unrecognized molecular mechanism that control the switch of NMDA receptor subunits in early postnatal brain development. Furthermore, we provide evidence that changes in the ratio of NMDA subunits GluN2A/GluN2B can also be detected in the synapse and mitochondria, which contributes to a persistent activation of the pro-survival ERK-CREB pathway and its downstream target genes. Collectively, these changes protect HIPK2 deficient neurons from mitochondrial toxins.