Activation of the G(alpha)q protein Gnaq in Mouse Hippocampus Rejuvenates the Aging Brain. Mus musculus strain:C57BL/6J

Cognitive decline is perhaps the most devastating aging loss. EGL-30/GNAQ and G(alpha)q signaling pathways are highly conserved between C. elegans and mammals. We find that activation of EGL-30 in aged worms at least triples memory span. Murine Gnaq is enriched in hippocampal excitatory neurons and declines with age. Expression of GNAQ gain-of-function significantly improved memory in aged mice: GNAQ(gf) in hippocampal neurons of 24-month-old mice restored their long-term memory and healthy behavior. Single-nucleus RNAseq revealed gene expression changes related to synaptic function, axon guidance, and learning and memory pathways. Several worm orthologs of mouse genes upregulated by GNAQ(gf) overexpression are required for EGL-30(gf)-dependent memory improvement. Thus, GNAQ/EGL-30 is a conserved regulator of age-related cognitive decline whose activation in aged animals rejuvenates cognitive function.