deletion drives cognitive deficits through mPFC interneuron dysfunction in a mouse model of schizophrenia.

Abstract

Cognitive dysfunction is a core feature of schizophrenia (SCZ), yet its mechanisms remain poorly understood. We investigated the functional role of(nuclear factor κB activating protein-like)-an SCZ risk-associated gene-and the single nucleotide polymorphism rs1635 in cognitive deficits related to SCZ. We usedtransgenic mouse models to explore the impact ofon SCZ-related cognitive deficits. NKAPL acts as a transcriptional repressor of the γ-aminobutyric acid (GABA) metabolizing enzyme succinic semialdehyde dehydrogenase (SSADH).deletion in medial prefrontal cortex (mPFC) interneurons led to increased SSADH levels, reduced GABA concentration in the synaptic cleft, impaired inhibitory synaptic transmission, and cognitive deficits. Furthermore, the rs1635 mutation (T153N) caused similar effects as theknockout. Reexpression of wild-type NKAPL or genetic knockdown of SSADH in mPFC interneurons restored the synaptic dysfunction and cognitive deficits inmice. Our study indicates the potential role of NKAPL and SSADH in mPFC interneurons in neuronal mechanisms of learning and memory in mice.