Cerebellar hyper-plasticity in the IB2 KO Mouse Model of ASD

Autismspectrum disorders (ASD) are pervasive neurodevelopmental disorders including syndromes with familial conditions. Among these, the Phelan-McDermid syndrome is associated with the co-deletion of SHANK3 and IB2 genes at the chromosome 22q terminus. Although much attention has been devoted to characterize SHANK3 mutations, very little is known about the role of IB2 in ASD. The IB2 protein is expressed at synapses and takes part to the NMDA receptor interactome in the postsynaptic densities. Here we further investigate the synaptic and circuit alterations in the IB2 KO mice, that already proved to be a reliable ASD model (Giza et al., 2010). Starting from the previously described enhancement of NMDA receptor-mediated synaptic currents at the cerebellarmossy fiber - granule cell synapse of IB2 KO mice, we investigated the impact of IB2 gene deletion on excitatory/inhibitory balance and synaptic plasticity in cerebellar cortex microcircuits. In particular, electrophysiological experiments showed increased granule cell excitability in IB2 KO compared to WT mice, together with a 3-fold enhanced NMDA receptor-mediated current. Using voltage sensitive dye imaging (VSDi), the spatial distribution of excitation (E) and inhibition (I) in the granular layer was assessed, showing an unbalanced E/I ratio in IB2 KO, mirrored in the distribution of the enhanced NMDA component of excitation in IB2 KO mice.Moreover, long-term potentiation (LTP) proved to be enhanced, while long-term depression (LTD) was reduced, in the IB2 KOcompared toWT. Interestingly, the spatial distribution in center (LTP) - surround (LTD) structures showed alterations in IB2 KO mice (with larger center and less deep surround) suggesting a shift from a classic Bmexican hat^ to a Bstove-pipe^ shape. These data show impressive cerebellar microcircuit alterations in the IB2 KO model, according to the growing number of evidence accounting for a major role of the cerebellum in ASD.