Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia

Abstract

The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters-glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids-and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate 'slow' (G-protein-coupled receptors) and 'fast' (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an 'associative' disorder-a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways-and may unify a number of currently competing hypotheses of SCZ pathophysiology.

Figure 1

Expanded version of Greengard’s neurotransmission integration scheme and its relation to 92 schizophrenia (SCZ) risk genes shown in red (see Table 1 for gene description).

Figure 2

Fold-enrichment plots for the following gene sets: ‘Ca²⁺ signaling toolkit’, ‘Ion channels’, ‘Ionotropic receptors for neurotransmitters’, ‘Metabotropic receptors for neurotransmitters’, ‘DARPP-32’ and ‘Dopamine pathway’. Shaded areas indicate confidence intervals.

Figure 3

Overlap of the present results with Greengard’s neurotransmission integration scheme. DARPP-32 integrates information via a variety of neurotransmitters (black) and neuroactive drugs (light blue). Only a subset of the identified schizophrenia risk genes is shown. Gene names are color coded according to the categories in Table 1: calcium signaling kit (red), ion channels except Ca²⁺ channels (yellow), ionotropic receptors and associated proteins (cyan), GPCR signaling proteins (green) and DARPP-32 integration pathway (blue). Red arrows indicate inhibition, green arrows indicate stimulation, and yellow arrow represents varied functions of the calcium signaling kit genes. Adapted from Greengard.