| Autism spectrum disorders (ASD) are associated with atypical sensory processing and sensory hypersensitivity, which lead to maladaptive behaviors, such as tactile defensiveness, and possibly contribute to symptoms of inattention, anxiety and learning disabilities. Disruptions in experience-dependent maturation of circuits during early brain development could give rise to altered sensory perception in ASD, but this has not been thoroughly investigated. Focusing on Fragile X Syndrome (FXS), the most common inherited form of autism, I tested the hypothesis that neural circuits in primary somatosensory (S1) cortex do not mature properly in response to sensory inputs. during critical and sensitive periods. Cortical dendritic spines in adult Fmr1 knockout (KO) mice, a model of FXS, are known to be unstable and insensitive to sensory input deprivation, but when this begins in development is not known. I used chronic in vivo two-photon microscopy to image layer 2/3 of S1 cortex of wild type (WT) and Fmr1 KO mice. Exposing 2-week-old WT mice to a brief (overnight) period of dramatically enhanced sensory experience led to a significant increase in spine density, whereas the numbers of spines in Fmr1 KO mice did not change. Next, I tested whether manipulations of inhibition could rescue cortical circuit defects in Fmr1 KO mice. I imaged intrinsic signals and found that single whisker maps in S1 cortex were abnormally large in Fmr1 KO mice starting at 2 weeks of age. Early intervention with the NKCC1 inhibitor, bumetanide for 2 weeks starting at birth corrected the size of whisker maps, even up to adulthood. I conclude that Fmr1 KO mice are unable to modulate post-synaptic dynamics in response to increased sensory input, at a time when sensory information processing first comes online in the cortex, which could play a role in altered sensory processing in FXS. Strategies that enhance inhibition could potentially rescue such circuit defects in FXS. |
