Altered cerebellar response to somatosensory stimuli in the Cntnap2 mouse model of autism.
2021
Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied sensory processing in the cerebellum in a mouse model of autism, knockout for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region upon electrical stimulation of the whisker pad in alert mice and found striking differences between WT and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of Purkinje cells. These changes were accompanied by altered intrinsic properties and morphological features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of autism core sensory deficits. Significance Statement Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. In support of this, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. One autism-linked gene associated to cerebellar dysfunction both in humans and animal models is CNTNAP2. In this work, we studied cerebellar integration of sensory information in the Cntnap2 mouse model of autism. We found striking differences between WT and Cntnap2 KO mice that indicate an altered cerebro-cerebellar connection. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of Purkinje cells. These alterations were accompanied by altered intrinsic properties and morphological features of these neurons. Although the mechanism of such deficits is not revealed, these data indicate that the Cntnap2 mouse model could be very valuable to identify the pathophysiological mechanisms of ASD core sensory deficits.
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