DYSREGULATION OF JANUS KINASE- AND MICROTUBULE-INTERACTING PROTEIN 1 (JAKMIP1) IS ASSOCIATED WITH ALTERED STAT3 SIGNALLING, SOMATOSENSORY CORTICAL HYPEREXCITABILITY, AND AUTISM-LIKE BEHAVIOURS

Autism Spectrum Disorder (ASD) is a genetically driven neurodevelopmental condition with molecular and circuit mechanisms remain incompletely understood. Janus kinase- and microtubule-interacting protein 1 (JAKMIP1) has been repeatedly implicated in ASD, and we previously showed that it regulates neuronal IL-6/STAT3 signalling and cytokine-induced neuritogenesis. However, how JAKMIP1-associated STAT3 alterations lead to in vivo cortical dysfunction and behavioural phenotypes remains unclear.Abnormal sensory experience is a core feature of ASD, we examined the primary somatosensory cortex (S1 barrel field; S1BF) in JAKMIP1 knockout (KO) mice. Molecular analyses revealed dysregulation of multiple established ASD-associated genes and a significant reduction in STAT3 expression in vivo, consistent with prior observations in JAKMIP1-deficient human neural cells. These changes were accompanied by increased neuronal, astrocytic, and microglial densities, elevated cell-type-specific marker expression, disrupted cortical lamination due to over-migration of deep-layer neurons into superficial layers, and enhanced excitatory synaptic transmission, resulting in a shift in excitatory/inhibitory balance toward cortical hyperexcitability.
JAKMIP1 KO mice exhibited reduced social motivation and increased repetitive behaviours. Repetitive jumping was robustly evoked by external sensory stimuli, consistent with altered somatosensory circuit function. Importantly, repeated low-dose administration of the STAT3 activator peptide Colivelin partially ameliorated social deficits and stimulus-induced repetitive jumping.
Together, these findings extend prior in vitro and human cell-based studies by demonstrating in vivo that JAKMIP1 deficiency alters STAT3 signalling, cortical circuitry, and ASD-associated behaviours. Our results support a functional role for STAT3-related pathways in JAKMIP1-linked neurodevelopment and underscore the need to define causal links between cytokine signalling, cortical circuits, and behaviour.