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

Devor, Anna; Andreassen, Ole Andreas; Wang, Yunpeng; Mäki-Marttunen, Tuomo; Smeland, Olav Bjerkehagen; Fan, Chun Chieh; Schork, Andrew J.; Holland, Dominic; Thompson, Wesley Kurt; Witoelar, Aree; Chen, Chi-Hua; Desikan, Rahul S.; McEvoy, Linda K.; Djurovic, Srdjan; Greengard, Paul; Svenningsson, Per; Einevoll, Gaute; Dale, Anders
Journal article; AcceptedVersion; Peer reviewed
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devor2017genetic.pdf (794.3Kb)
Year
2017
Permanent link
http://urn.nb.no/URN:NBN:no-62703

CRIStin
1472956

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Appears in the following Collection
  • Institutt for klinisk medisin [5349]
  • Fysisk institutt [2260]
  • CRIStin høstingsarkiv [15141]
Original version
Molecular Psychiatry. 2017, 22 (6), 792-801, DOI: http://dx.doi.org/10.1038/mp.2017.33
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.
 
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