HERC1 Loss of Function Causes a Developmental Disorder with Impaired Hippocampal Function

Pathogenic variants in HERC1 are associated with a syndromic neurodevelopmental disorder characterized by macrocephaly, developmental delay, intellectual disability, and psychomotor dysfunction. Although genetic and molecular studies suggest a loss-of-function mechanism, definitive in vivo evidence that HERC1 deficiency is sufficient to cause neurodevelopmental abnormalities is lacking. Using a HERC1 knockout mouse model, we investigated the behavioural, neuronal, and synaptic consequences of complete HERC1 loss. HERC1 deficiency caused motor coordination and cognitive deficits in both sexes, while male mutants additionally displayed hyperactivity and increased anxiety-like behaviour. Histological analyses revealed selective hippocampal abnormalities, including disruption of dentate gyrus organization, whereas Purkinje cells survival and cerebellar compartmentalization remained preserved. HERC1-deficient mice exhibited a marked increase in hippocampal GABAergic interneurons, impaired maturation of dendritic spines in CA1 pyramidal neurons, and altered adult neurogenesis, indicating widespread defects in hippocampal circuit organization. Consistent with these structural abnormalities, glutamatergic synaptic components were significantly altered throughout the hippocampus. These molecular changes showed a sex-dependent pattern, with predominantly presynaptic defects in males and postsynaptic alterations in females. Despite these differences, whole-cell recordings revealed a common functional phenotype in both sexes. At both mossy fibre-CA3 and Schaffer collateral-CA1 synapses, HERC1-deficient neurons exhibited a progressive inability to sustain excitatory neurotransmission during repetitive stimulation, resulting in impaired steady-state glutamatergic transmission. Together, these findings demonstrate that loss of HERC1 function is sufficient to produce a neurodevelopmental phenotype and identify HERC1 as a critical regulator of hippocampal circuit assembly and function. Our results provide mechanistic insight into the pathogenesis of HERC1-associated disorders and establish the Herc1 knockout mouse as a preclinically relevant model for investigating disease mechanisms and therapeutic approaches.