Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia

Abstract

We sought to obtain novel insights into schizophrenia pathogenesis by exploiting the association between the disorder and chromosomal copy number (CNV) burden. We combined data from 5,745 cases and 10,675 controls with other published datasets containing genome-wide CNV data. In this much-enlarged sample of 11,355 cases and 16,416 controls, we show for the first time that case CNVs are enriched for genes involved in GABAergic neurotransmission. Consistent with non-genetic reports of GABAergic deficits in schizophrenia, our findings now show disrupted GABAergic signaling is of direct causal relevance, rather than a secondary effect or due to confounding. Additionally, we independently replicate and greatly extend previous findings of CNV enrichment among genes involved in glutamatergic signaling. Given the strong functional links between the major inhibitory GABAergic and excitatory glutamatergic systems, our findings converge on a broad, coherent set of pathogenic processes, providing firm foundations for studies aimed at dissecting disease mechanisms.

Figure 1

Functional Interactions between Neuronal Complexes Implicated in Schizophrenia Supporting and extending previous studies (Fromer et al., 2014; Kirov et al., 2012; Purcell et al., 2014), our analyses indicate a contribution to schizophrenia from ARC, NMDAR network, PSD-95, and GABA_A neuronal complexes. Although not strongly associated here, targets of the translational repressor FMRP have previously been found to be enriched in CNVs and rare de novo small mutations in individuals with schizophrenia (Fromer et al., 2014; Purcell et al., 2014; Szatkiewicz et al., 2014). This figure summarizes the relationship between these sets of molecules and their roles in synaptic signaling and plasticity. (A) PSD-95 complexes are an important component of the postsynaptic scaffold at glutamatergic synapses, linking a wide range of channels and receptors including NMDARs (top left). Calcium influx via the NMDAR drives multiple downstream pathways (red arrows): local signaling regulates induction of synaptic potentiation, while activation of ARC transcription via signaling to the nucleus is required for the long-term maintenance of synaptic changes. Once transcribed, mRNAs encoding ARC and other synaptic proteins are inactivated via association with FMRP and transported to synaptodendritic sites of protein synthesis. Here, activity-dependent dissociation of FMRP releases transcripts from translational repression allowing protein synthesis and incorporation into active synapses. (B) NMDAR activation requires both presynaptic glutamate release and strong post-synaptic depolarization, which may be induced by the back-propagation of action potentials. Influx of chloride ions via GABA receptors attenuates the dendritic transmission of excitation, inhibiting action potential generation and back-propagation. Phasic firing of synaptic GABA receptors plays a key role in establishing neural oscillations, required for the coordination of distributed functional networks. Tonic GABA receptors also modulate excitatory currents and oscillatory neuronal behavior, being responsive to local network activity via the overspill of GABA from synaptic receptors and its release/uptake by glia (blue cell in A). For simplicity all receptors are shown acting upon a single neuron; in reality, their interplay is distributed across multiple neuronal cell types, e.g., tonic GABA currents also modulating synaptic GABA release from interneurons.