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

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. Herein, we exploited a combination of whole-cell patch-clamp recordings with voltage sensitive dye imaging (VSDi) in acute cerebellar slices in WT and IB2 KO mice to investigate single-neuron and microcircuit properties. 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. The granular layer of these mice revealed severe alterations in synaptic transmission, neuronal excitation and long-term synaptic plasticity. A 2.5-times larger NMDA receptormediated current in IB2 KO granule cells enhanced synaptic plasticity (WT = 20.4 ± 4.2 %, n=12 vs. IB2 KO = 107.7 ± 44.4, n=9; p<0.05) along with the excitatory/inhibitory (E/I) balance (WT = 0.98 ± 0.27, n=6 vs. IB2 KO = 2.78 ± 0.32, n=7; p<0.01). At the same time, the spatial organization of granular layer responses to mossy fiber inputs shifted from a "Mexican hat" to a "stovepipe hat" profile, with stronger excitation in the core (WT = 12.9 ± 1.7 μm vs. IB2 KO = 29.5 ± 4.9 μm, n=5 for both; p<0.01) and limited inhibition in the surround (WT/KO ratio IWT/ KO = 2.83 ± 0.17, n=5). The IB2 KO mouse model therefore configures a complex cerebellar synaptopathy centered on NMDA receptor gain of function, that in several respects resembles alterations also observed in cortical minicolumns. The profound changes of signal processing at the cerebellar input stage unveil a possible new mechanism contributing to the pathogenesis of autistic-like behavior.