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

• Published in: The Journal of neuroscience Vol. 38; no. 16; pp. 4006 - 4019
• Main Authors: Shang, Yulei, Zhang, Jiasheng, Huang, Eric J
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 18.04.2018
• Subjects: Apoptosis; Brain; c-Jun protein; Cell death; Cell interactions; Cell survival; Cyclic AMP response element-binding protein; Glutamic acid receptors (ionotropic); HIPK2 protein; Mental disorders; Mitochondria; N-Methyl-D-aspartic acid receptors; Proteins; Receptors; Toxins; Transcription factors
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3577-17.2018

NMDA ( -methyl -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 and mice, we showed that the HIPK2-JNK-c-Jun pathway is important in suppressing the transcription of and , 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 and 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 neurons to cell death induced by mitochondrial toxins. 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.