Inhba, Homer1 and Bdnf are major targets of transcriptomic dysregulation by neurodegenerative disease-associated excitotoxic NMDA receptor signaling.

Synaptic activity-regulated gene expression supports neuroprotection, plasticity, and memory. The transcription factor CREB is central to these processes. It is activated by synaptic NMDA receptors but inactivated by excitotoxic extrasynaptic NMDAR (esNMDAR) signaling. Using primary hippocampal neurons, we modeled neurodegeneration and found that esNMDAR activation, which causes CREB shut-off and inactivation of the ERK/MAPK-ELK1/SRF pathway, extensively distorted control of synaptic activity over transcription. This resulted in the suppression of key neuroprotective genes, in particular Inhba and Bdnf, but also of genes involved in synaptic function (Homer1, Btg2, Mir132, Mir212) and transcription factor genes (Atf3, Egr1, Fos, Npas4). In a Huntington's disease (HD) mouse model, treatment with memantine or targeting the NMDAR/TRPM4 complex with FP802 restored gene expression, notably Inhba, Homer1 and Bdnf, and attenuated the decrease of the HD disease marker Ppp1r1b (DARPP-32). These findings identify esNMDAR-driven transcriptional dysregulation as a key pathomechanism in neurodegenerative disease, supporting inhibition of esNMDAR-signaling as a promising therapeutic approach.