Distinct forms of spinal cord inhibition regulate tactile reactivity in mouse models of autism spectrum disorders

Abstract

Individuals with autism spectrum disorders (ASDs) frequently report altered reactivity to sensory stimuli, with many individuals displaying over-responsivity to tactile stimuli. Genetic factors explain much of the risk for ASDs, and ASD-associated genes function in compartments of both the central and peripheral nervous systems to regulate sensitivity to sensory input. Appropriate feedback (or presynaptic) inhibition of peripheral somatosensory neurons is critical for normal touch reactivity in adult mice, and loss of PSI drives tactile over-reactivity in multiple mouse models of ASD. In this study we report that genetic ASD models in which feedforward inhibitory (FFI) control of sensory inputs onto spinal cord neurons is disrupted also display tactile over-reactivity in adulthood. Interestingly, we observed that ASD models that exhibit deficits in PSI of sensory neurons are over-reactive to light touch from birth, whereas animals with disruption to FFI of spinal cord neurons show normal tactile reactivity until late stages of postnatal development. Furthermore, though both PSI and FFI are critical for normal tactile reactivity in adults, animals that exhibit disruptions to PSI display aberrant anxiety-like behaviors, as previously described, but the same is not observed in mice with altered spinal cord FFI. Addressing the cellular and synaptic mechanisms underlying the development of PSI and FFI of somatosensory input to the spinal cord, we find that the differences in onset of tactile hyper-reactivity as well as comorbid behavioral consequences relate to the observation that PSI and FFI in the spinal cord mature at different stages: PSI is established neonatally, whereas FFI develops late postnatally. These findings support the idea that the precise timing of altered modes of inhibition of somatosensory input to the spinal cord determines the timing of aberrant sensory reactivity, and this in turn is a critical determinant in the genesis of other, comorbid ASD-associated behaviors such as anxiety.