Autism spectrum disorder (ASD) is frequently accompanied by sensory and motor abnormalities, including impaired balance, postural control, and spatial orientation, that are often attributed largely to altered central circuitry. Emerging evidence, however, suggests that peripheral sensory dysfunction can also shape ASD related behavioral phenotypes. Here, we tested whether loss of the ASD associated gene Cntnap2 alters vestibular signaling in Cntnap2-/- mice. Developmental transcriptomic analysis showed that Cntnap2 is expressed in vestibular sensory organs and increases during the first postnatal month, coincident with vestibular pathway maturation. Vestibular sensory evoked potentials revealed reduced response amplitudes and prolonged latencies in Cntnap2-/- mice, indicating impaired peripheral afferent responses to transient linear acceleration. Cntnap2-/- mice also showed delayed contact righting, reduced ocular counter roll, and increased hindlimb slips and compensatory tail excursions during balance beam walking, whereas rotational vestibulo-ocular reflex gain and phase were preserved. These vestibular and balance abnormalities were accompanied by reduced novel arm preference in the Y maze and severe impairment of Barnes maze acquisition, consistent with impaired spatial learning. Together, these findings identify Cntnap2 as a regulator of vestibular sensory signaling and support a model in which disrupted peripheral vestibular input, likely acting together with central effects of Cntnap2 loss, contributes to sensorimotor and spatial cognitive phenotypes relevant to ASD.
Shu, Y., Chen, Y., Zhou, D., Deng, X., Florea, L. D., Deemyad, T., Sadeghi, S. G.
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