Schizophrenia as a GSK-3 dysregulation disorder.
Converging evidence suggests that the regulation of glycogen synthase kinase 3 (GSK-3) might be important in schizophrenia. Atypical and typical antipsychotic drugs alter GSK-3 activity, as do drugs that induce psychosis. GSK-3 regulatory pathways are altered in schizophrenia, and many of the genes associated with schizophrenia directly or indirectly regulate GSK-3 activity. We propose a variant on the neurodevelopment and dopamine hypotheses of schizophrenia, whereby (i) an early dysfunction in GSK-3 regulation has neurodevelopmental consequences that predispose to disease and (ii) dysfunction in GSK-3 regulation in the adult brain alters dopamine signalling events, causing psychotic symptoms and cognitive dysfunction. If, as we suggest, GSK-3 regulation is crucial to schizophrenia, the Wnt and insulin signalling pathways become targets for therapy.
Lovestone
Simon
S
Departments of Psychological Medicine and Neuroscience Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK. s.lovestone@iop.kcl.ac.uk
Killick
Richard
R
Di Forti
Marta
M
Murray
Robin
R
D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D012559:Schizophrenia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology
D038362:Glycogen Synthase Kinase 3