NPAS3-regulated astrocyte mitochondria bioenergetics is required for cognition

The basic helix-loop-helix (bHLH) transcription factor neuronal PAS domain protein 3 (NPAS3) provides transcriptional regulation of metabolic pathways, and despite its name is highly expressed in astrocytes. NPAS3 variants have been associated with cognitive dysfunction in several neuropsychiatric conditions, but the underlying brain cell type-specific mechanisms remain obscure. Here, we report that NPAS3 is a key regulator of mitochondria bioenergetics in astrocytes. Selective deletion of Npas3 in mature murine astrocytes decreases expression of Slc25a18 and its protein product, mitochondrial glutamate carrier 2, leading to reduced oxidative phosphorylation and lactate production in astrocytes. This deficit subsequently causes reduced excitability, dendritic spine density, and dendritic arborization of medial prefrontal cortex pyramidal neurons. Mice with Npas3-deficient cortical astrocytes exhibit impaired trace fear conditioning, which is rescued by lactate treatment. Thus, the present study demonstrates a mechanistic link between NPAS3-dependent astrocyte mitochondria bioenergetics and cognitive function and provides insights for glia-targeting treatment of cognitive dysfunction in neuropsychiatric disease.