NPAS3-regulated astrocyte mitochondrial bioenergetics is required for cognition

The basic helix-loop-helix transcription factor neuronal PAS (Per, Arnt, Sim) domain protein 3 (NPAS3) provides transcriptional regulation of metabolic pathways and is highly expressed in astrocytes. NPAS3 variants have been associated with cognitive dysfunction under several neuropsychiatric conditions, but the underlying brain cell type-specific mechanisms remain obscure. Here, we report that NPAS3 is a key regulator of mitochondrial bioenergetics in astrocytes in the mouse brain. Selective deletion of Npas3 in mature astrocytes decreases expression of mitochondrial glutamate carrier 2 involved in glutamate oxidation, leading to reduced oxidative phosphorylation and lactate production in astrocytes. This deficit reduces intrinsic excitability, dendritic spine density, and excitatory synaptic transmission of medial prefrontal cortex (mPFC) pyramidal neurons. Mice with Npas3-deficient mPFC astrocytes exhibit impaired trace fear conditioning, which is rescued by lactate treatment. Thus, the present study demonstrates a mechanistic link between NPAS3-dependent astrocyte mitochondrial bioenergetics and cognitive function and provides insights for glia-targeting treatment of cognitive dysfunction in neuropsychiatric disease.