Sensory over-responsivity and aberrant plasticity in cerebellar cortex in a mouse model of syndromic autism

Abstract Background Autism spectrum disorder (ASD) patients often show altered responses to sensory stimuli as well as motor deficits, including an impairment of delay eyeblink conditioning (EBC), which involves integration of sensory signals in the cerebellum. Here, we identify abnormalities in parallel fiber (PF) and climbing fiber (CF) signaling in mouse cerebellar cortex that may contribute to these pathologies. Methods We use a mouse model for the human 15q11-13 duplication (patDp/+) and studied responses to sensory stimuli in Purkinje cells (PCs) from awake mice using two-photon imaging of GCaMP6f signals. Moreover, we examined synaptic transmission and plasticity using in vitro electrophysiological, immunohistochemical and confocal microscopic techniques. Results We find that spontaneous and sensory-evoked CF-calcium transients are enhanced in patDp/+ PCs and aversive movements are more severe across sensory modalities. We observe increased expression of the synaptic organizer neurexin 1 (Nrxn1) at CF synapses, and ectopic spread of these synapses to fine dendrites. CF-EPSCs recorded from PCs are enlarged in patDp/+ mice, while responses to PF stimulation are reduced. Confocal measurements show reduced PF+CF-evoked spine calcium transients, a key trigger for PF long-term depression (LTD), one of several plasticity types required for EBC learning. LTD is impaired in patDp/+ mice, but is rescued upon pharmacological enhancement of calcium signaling. Conclusions Our findings suggest that this genetic abnormality causes a pathological inflation of CF signaling, possibly resulting from enhanced Nrxn1 expression, with consequences for the representation of sensory stimuli by the CF input and for PF synaptic organization and plasticity.