to a lesser extent ARC protein, complexes in the aetiology and pathogenesis of the disorder, both of which are involved in NMDA signal transduction. NMDA receptor signalling regulates induction of multiple forms of synaptic plasticity,46 with local synthesis of ARC central to synaptic remodelling and the long-term maintenance of synaptic changes.47 Our finding that 12 out of the 34 case de novos impact on ARC and/or NMDAR complexes, supported by robust statistical analyses, suggest that disruption of NMDA signalling plays a key role in at least some cases of schizophrenia. As noted above, our findings do not exclude a role for mutations in other post- or pre-synaptic complexes, and given the close functional relationship between different synaptic components, we might expect pathology at a number of different points to play a role. Indeed, the robust association between NRXN1 deletions and schizophrenia48 points to presynaptic disruption in some cases, a hypothesis further supported by enrichment for case de novos in the GO category ‘synaptic vesicle membrane' after adjustment for ARC and NMDAR. Our findings delineate a circumscribed set of largely postsynaptic proteins and functions that warrant further functional analysis in model systems.
