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.