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.

A unified computational model for cortical post-synaptic plasticity

“…Moreover, our model can be used for initial testing of hypotheses concerning dysfunctions (including chemical and genetic manipulations) of many intracellular signalling proteins and their role in impairments of cortical synaptic plasticity. By altering the initial concentrations or reaction rates of various species according to disease-associated functional genetics data, the model can be used to provide insights into the disease mechanisms of mental disorders that express both genetic disposition of post-synaptic signalling pathways and plasticity-related phenotypes, such as schizophrenia [Devor et al, 2017]. 6 Financial disclosures…”

Association Between Polymorphisms of the Complement 3 Gene and Schizophrenia in a Han Chinese Population

“…Schizophrenia (SCZ) is a severe mental disorder that affects approximately 0.5–1% of the population worldwide and has a profound impact on society and the economy [1, 2]. SCZ is highly prevalent among young adults [3], and its incidence rate is slightly higher in males than in females (1.4: 1) [4].…”

Use of tobacco in schizophrenia: A double‐edged sword

“…The potential neurobiological mechanism involved in this process is shown in Figure . An established hypothesis proposed that neurotransmitter dysfunction (e.g., dopamine, glutamate, gamma‐aminobutyric acid, and acetylcholine) is the important pathological mechanism of schizophrenia (Devor et al, ; Dineley, Pandya, & Yakel, ; McCutcheon, Abi‐Dargham, & Howes, ; Wierońska & Pilc, ). Nicotine—the addictive ingredient in tobacco—binds to the nicotinic acetylcholine receptors, which are expressed in the human brain and influence neurotransmitter systems, thereby normalizing neurotransmitter dysfunction and improving disease (Lucatch et al, ).…”