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

Abstract

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. 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.

Diverse Neuron Properties and Complex Network Dynamics in the Cerebellar Cortical Inhibitory Circuit

“…The functional relevance of this inhibitory organization has recently been described through multi-electrode array recordings and voltage-sensitive dye imaging (Mapelli and D’Angelo, 2007; Mapelli et al, 2009; D’Angelo et al, 2013). Previous investigations in vitro have shown that lateral inhibition in the GL originates a center-surround organization of granule cell activity (Mapelli and D’Angelo, 2007; D’Angelo, 2008; Soda et al, 2019), characterized by prevailing excitation in the core, surrounded by an inhibited area. The center-surround pattern is generated as follows: when the MFs discharge in bursts, both granule cells and Golgi cells are activated in the same region.…”

“…The result is LTP in the center and LTD in the surround, so that LTP and LTD assume a center-surround organization. Modified from Soda et al (2019). (b) MLIs provide the substrate for lateral inhibition of PCs by virtue of the orthogonal arrangement of excitation and inhibition onto PCs: the PFs run coronally, whereas the axons of MLIs run sagittally.…”

The Optogenetic Revolution in Cerebellar Investigations

“…Recent anatomical, structural and functional evidence has revealed that cerebellar activation is associated with addiction, social cognition and emotional processing [90][91][92][93]. Furthermore, cerebellar lesions are implicated in cognitive disorders and abnormal social behavior such as in autism spectrum disorders (ASD), cognitive affective syndrome, schizophrenia and epilepsy [93][94][95][96][97][98][99][100]. Notably, ASD patients report both motor dysfunctions together with non-motor symptoms, suggesting that cerebellar impairment might indeed contribute to both [95,100,101], likely depending on the connected brain areas [102].…”

“…Furthermore, cerebellar lesions are implicated in cognitive disorders and abnormal social behavior such as in autism spectrum disorders (ASD), cognitive affective syndrome, schizophrenia and epilepsy [93][94][95][96][97][98][99][100]. Notably, ASD patients report both motor dysfunctions together with non-motor symptoms, suggesting that cerebellar impairment might indeed contribute to both [95,100,101], likely depending on the connected brain areas [102]. In non-human primates, tract-tracing investigations have demonstrated that topographically distinct regions (called output channels) of the DCN project to different cortical areas: with dorsal parts sending efferent fibers to the motor cortex and ventral parts to the prefrontal and parietal cortexes, which are generally involved in cognitive and higher-order executive functions [103,104].…”

Glutamatergic Dysfunction and Synaptic Ultrastructural Alterations in Schizophrenia and Autism Spectrum Disorder: Evidence from Human and Rodent Studies

“…Adding another layer of complexity, a mouse model of Phelan-McDermid syndrome causing autistic phenotypes with a deficiency of mitogen-activated protein kinase 8 interacting protein 2 (MAPK8IP2/IB2), which plays an important role in regulating the ratio of AMPARs to NMDARs at glutamate synapses, revealed no synaptic ultrastructure alterations of cerebellar glutamatergic synapses and featured normal synaptic clefts and postsynaptic densities and abundant presynaptic vesicles [252]. However, despite the normal ultrastructure, a larger NMDAR-mediated current and enhanced intrinsic excitability and LTP were revealed in this mouse model [253].…”