Hyper-excitability and hyper-plasticity disrupt cerebellar signal transfer in the IB2 KO mouse model of autism

Teresa Soda, Lisa Mapelli, Francesca Locatelli, Laura Botta, Mitchell Goldfarb, Francesca Prestori, Egidio D'Angelo

Research output: Contribution to journalArticlepeer-review

Abstract

Autism spectrum disorders (ASD) are pervasive neurodevelopmental conditions that often involve mutations affecting synaptic mechanisms. Recently, the involvement of cerebellum in ASD has been suggested but the underlying functional alterations remained obscure. We investigated single-neuron and microcircuit properties in IB2 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 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 was remarkably increased. These results show for the first time that hyper-excitability and hyper-plasticity disrupt signal transfer in the granular layer of IB2 KO mice supporting cerebellar involvement in the pathogenesis of ASD.SIGNIFICANCE STATEMENTThis paper shows for the first time a complex set of alterations in the cerebellum granular layer of a mouse model (IB2 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 hyper-activity, hyper -plasticity and hyper-excitability. 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 supports recent theories suggesting the involvement of cerebellum in autism spectrum disorders.

Original languageEnglish
Pages (from-to)2383-2397
JournalJournal of Neuroscience
Volume39
Issue number13
DOIs
Publication statusPublished - May 29 2019

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