Pathogenic KIF5C mutation disrupts dendritic spine maturation and mitochondrial trafficking in neurodevelopmental disorders.

Abstract

KIF5C, a kinesin-1 motor protein critical for neuronal cargo transport, has been clinically associated with developmental delay and intellectual disability (DD/ID), although its pathogenic mechanisms are yet to be elucidated. Building on our prior identification of a de novo heterozygous KIF5C variant in a patient with DD/ID, a conditional knock-in mouse model was constructed to determine disease pathogenesis. The mutant mice exhibited core clinical phenotypes, including growth retardation, microcephaly, and deficits in social and spatial memory. Electrophysiological recordings revealed a decreased frequency of miniature excitatory postsynaptic currents, impaired long-term potentiation, and altered presynaptic vesicle release probability. Mechanistically, hippocampal neurons displayed decreased mature dendritic spines and impaired axonal mitochondrial transport, collectively contributing to diminished excitatory neurotransmission. Nonetheless, the overexpression of KIF5C in hippocampal CA1 neurons enhanced memory performance and excitatory synaptic transmission in the mutant mice. Overall, these findings establish that KIF5C dysfunction disrupts dendritic spine maturation at the postsynaptic terminal, axonal mitochondrial transport, and presynaptic vesicle release. Thus, a critical cellular mechanism underlying DD/ID pathogenesis has been identified in this research, opening novel therapeutic avenues.