1. Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia
- Author
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Devor, A, Andreassen, OA, Wang, Y, Mäki-Marttunen, T, Smeland, OB, Fan, C-C, Schork, AJ, Holland, D, Thompson, WK, Witoelar, A, Chen, C-H, Desikan, RS, McEvoy, LK, Djurovic, S, Greengard, P, Svenningsson, P, Einevoll, GT, and Dale, AM
- Subjects
Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Schizophrenia ,Human Genome ,Genetics ,Mental Health ,Serious Mental Illness ,Biotechnology ,Brain Disorders ,Neurosciences ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Mental health ,Brain ,Dopamine ,Dopamine and cAMP-Regulated Phosphoprotein 32 ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Humans ,Multifactorial Inheritance ,Polymorphism ,Single Nucleotide ,Receptors ,Ionotropic Glutamate ,Receptors ,Metabotropic Glutamate ,Risk Factors ,Signal Transduction ,Synaptic Transmission ,gamma-Aminobutyric Acid ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Clinical sciences ,Biological psychology ,Clinical and health psychology - 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.
- Published
- 2017