Sensory Over-responsivity and Aberrant Plasticity in Cerebellar Cortex in a Mouse Model of Syndromic Autism.

Autor:	Simmons DH; Department of Neurobiology, University of Chicago, Chicago, Illinois., Busch SE; Department of Neurobiology, University of Chicago, Chicago, Illinois., Titley HK; Department of Neurobiology, University of Chicago, Chicago, Illinois.; Department of Nursing, University of Alberta, Edmonton, Alberta, Canada., Grasselli G; Department of Neurobiology, University of Chicago, Chicago, Illinois.; Istituto Italiano di Tecnologia, Center for Synaptic Neuroscience and Technology, Genoa, Italy.; IRCC Ospedale Policlinico San Martino, Genoa, Italy., Shih J; Department of Neurobiology, University of Chicago, Chicago, Illinois., Du X; Department of Neurology, University of Chicago, Chicago, Illinois., Wei C; Department of Neurology, University of Chicago, Chicago, Illinois., Gomez CM; Department of Neurology, University of Chicago, Chicago, Illinois., Piochon C; Department of Neurobiology, University of Chicago, Chicago, Illinois., Hansel C; Department of Neurobiology, University of Chicago, Chicago, Illinois.
Jazyk:	angličtina
Zdroj:	Biological psychiatry global open science [Biol Psychiatry Glob Open Sci] 2021 Oct 01; Vol. 2 (4), pp. 450-459. Date of Electronic Publication: 2021 Oct 01 (Print Publication: 2022).
DOI:	10.1016/j.bpsgos.2021.09.004
Abstrakt:	Background: Patients with autism spectrum disorder often show altered responses to sensory stimuli as well as motor deficits, including an impairment of delay eyeblink conditioning, which involves integration of sensory signals in the cerebellum. Here, we identify abnormalities in parallel fiber (PF) and climbing fiber (CF) signaling in the mouse cerebellar cortex that may contribute to these pathologies. Methods: We used a mouse model for the human 15q11-13 duplication (patDp/+) and studied responses to sensory stimuli in Purkinje cells 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 found that spontaneous and sensory-evoked CF-calcium transients are enhanced in patDp/+ Purkinje cells, and aversive movements are more severe across sensory modalities. We observed increased expression of the synaptic organizer NRXN1 at CF synapses and ectopic spread of these synapses to fine dendrites. CF-excitatory postsynaptic currents recorded from Purkinje cells 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, one of several plasticity types required for eyeblink conditioning learning. Long-term depression is impaired in patDp/+ mice but is rescued on 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. (© 2021 The Authors.)
Databáze:	MEDLINE
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