Disruption of the SIRT6-REST-GluN2A pathway impairs sociability and memory via excitation/inhibition balance

The sirtuin (SIRT) family of NAD⁺-dependent deacetylases has been implicated in aging, cell survival, and neurodegenerative processes. Recently, SIRT6 has been reported to be important in learning and memory. However, the functions of SIRT6 in excitatory and inhibitory neurons remain largely unknown. Here we provide evidence that neuronal SIRT6 contributes to the regulation of excitatory/inhibitory (E/I) balance in the brain. Conditional knockout of SIRT6 in excitatory neurons impaired associative fear memory, disrupted NMDA receptor-dependent transmission, and was accompanied by reduced hippocampal long-term potentiation (LTP). Conditional knockout of SIRT6 in inhibitory neurons increased associative fear memory and elevated E/I ratio of excitatory neurons. Mechanistically, SIRT6 suppresses transcription of the repressor REST by regulating histone H3K9 and H3K56 acetylation at the Rest promoter, thereby relieving REST-mediated repression of the schizophrenia risk gene Grin2a , which encodes the NMDA receptor subunit GluN2A. Pharmacological activation of NMDA receptors or knockdown of REST partially ameliorated behavioral deficits. These new findings identify SIRT6 as an epigenetic modulator of E/I balance and highlight its potential role in regulating circuit function and behavior.