Phenotypic assessment of Stxbp1 haploinsufficiency reveals neurological disabilities in serotoninergic system.

Abstract

STXBP1 (Syntaxin-binding protein 1) is a presynaptic SNARE complex regulator essential for neurotransmitter release. De novo heterozygous mutations in Stxbp1 represent one of the most common genetic causes of early onset epileptic encephalopathies (STXBP1 related disorders, STXBP1-RD). STXBP1 protein is ubiquitously expressed across all neuronal populations. While impaired synaptic E/I balance is established, neuronal subtype-specific mechanisms of STXBP1-RD remain poorly defined. Here, we deployed multi-level genetic models to delineate the neuronal and behavioral consequences of STXBP1 insufficiency. In C. elegans, systemic evaluation of STXBP1 (UNC-18) deficiency revealed deficits in serotonergic neurons, manifested as progressive dendritic atrophy. In a new established Stxbp1 haploinsufficient mouse model, we confirmed serotonergic system dysfunction, characterized by reduced serotonergic neuron numbers, decreased 5-HT levels, and compensatory upregulation of serotonin receptors. Finally, mice with serotonergic neuron-specific Stxbp1 haploinsufficiency recapitulated a subset of neurological phenotypes. Together, this study reveals the underestimated serotonergic dysfunction as a pathological component of STXBP1-RD.