Nervous system reduction in branched-chain amino acid metabolism disrupts hippocampal neurogenesis and memory

Abstract: A role for macronutrient metabolism in learning and memory is supported by numerous epidemiological studies. The Ppm1k gene encodes the branched-chain keto acid dehydrogenase (BCKDH) phosphatase that promotes the metabolism of branched-chain amino acids (BCAA). Here we show that nervous system deletion of Ppm1k in mice increases BCAA levels in brain tissue but not in plasma. These mice have significant impairments in working memory accompanied by a robust accumulation of DCX+/NeuroD1+ immature neurons within the dentate gyrus granule cell layer. Through single cell RNA sequencing and pathway analysis we identified substantial increases in transit-amplifying cells and immature neurons along with activated hedgehog signaling in Ppm1k deficient primary neural stem cells (NSCs). Inhibition of mTOR signaling reversed the effects of Ppm1k deletion on neuronal progenitor gene activation in primary NSCs. Together our findings uncover a new molecular link between BCAA metabolism, hippocampal neurogenesis, and cognitive performance.