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J Neurosci. 2019 Mar 27;39(13):2383-2397. doi: 10.1523/JNEUROSCI.1985-18.2019. Epub 2019 Jan 29.

Hyperexcitability and Hyperplasticity Disrupt Cerebellar Signal Transfer in the IB2 KO Mouse Model of Autism.

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Departments of Brain and Behavioral Sciences.
Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi, 00184 Rome, Italy.
Biology and Biotechnology "L. Spallanzani," University of Pavia, 27100 Pavia, Italy.
Department of Biological Sciences, Hunter College, New York, New York 10065, and.
Departments of Brain and Behavioral Sciences,
Brain Connectivity Center, C. Mondino National Neurological Institute, 27100 Pavia, Italy.


Autism spectrum disorders (ASDs) are pervasive neurodevelopmental conditions that often involve mutations affecting synaptic mechanisms. Recently, the involvement of cerebellum in ASDs has been suggested, but the underlying functional alterations remained obscure. We investigated single-neuron and microcircuit properties in IB2 (Islet Brain-2) KO mice of either sex. The IB2 gene (chr22q13.3 terminal region) deletion occurs in virtually all cases of Phelan-McDermid syndrome, causing autistic symptoms and a severe delay in motor skill acquisition. IB2 KO granule cells showed a larger NMDA receptor-mediated current and enhanced intrinsic excitability, raising the excitatory/inhibitory balance. Furthermore, the spatial organization of granular layer responses to mossy fibers shifted from a "Mexican hat" to a "stovepipe hat" profile, with stronger excitation in the core and weaker inhibition in the surround. Finally, the size and extension of long-term synaptic plasticity were remarkably increased. These results show for the first time that hyperexcitability and hyperplasticity disrupt signal transfer in the granular layer of IB2 KO mice, supporting cerebellar involvement in the pathogenesis of ASD.SIGNIFICANCE STATEMENT This article shows for the first time a complex set of alterations in the cerebellum granular layer of a mouse model [IB2 (Islet Brain-2) KO] of autism spectrum disorders. The IB2 KO in mice mimics the deletion of the corresponding gene in the Phelan-McDermid syndrome in humans. The changes reported here are centered on NMDA receptor hyperactivity, hyperplasticity, and hyperexcitability. These, in turn, increase the excitatory/inhibitory balance and alter the shape of center/surround structures that emerge in the granular layer in response to mossy fiber activity. These results support recent theories suggesting the involvement of cerebellum in autism spectrum disorders.


NMDA receptor; autism; cerebellum; excitatory/inhibitory balance; hyperplasticity

[Available on 2019-09-27]

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