Deficits in Syntaxin 1 Phosphorylation in Schizophrenia Prefrontal Cortex

• Published in: Biological psychiatry (1969) Vol. 67; no. 3; pp. 208 - 216
• Main Authors: Castillo, Max A, Ghose, Subroto, Tamminga, Carol A, Ulery-Reynolds, Paula G
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.02.2010; Elsevier
• Subjects: Adult; Adult and adolescent clinical studies; Aged; Aged, 80 and over; Animals; Antipsychotic Agents - pharmacology; Antipsychotic drugs; Biological and medical sciences; Casein Kinase II - metabolism; Cohort Studies; Female; Gene Expression Regulation - physiology; Humans; Immunoprecipitation - methods; Male; Medical sciences; Mice; Mice, Inbred C57BL; Middle Aged; Neuropharmacology; Nucleolin; Pharmacology. Drug treatments; phospho-specific antibody; Phosphoproteins - metabolism; Phosphoric Monoester Hydrolases - pharmacology; Phosphorylation; post mortem; Postmortem Changes; prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Psychiatry; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - metabolism; RNA-Binding Proteins - metabolism; Schizophrenia; Schizophrenia - pathology; SNARE; SNARE Proteins - metabolism; Stx 1; Syntaxin 1 - metabolism; Time Factors; Young Adult; Stx 1; post mortem; Antipsychotic drugs; phospho-specific antibody; prefrontal cortex; SNARE; Phosphorylation; Neuroleptic; Psychotropic; Central nervous system; Postmortem; Pharmacotherapy; Schizophrenia; Prefrontal cortex; Encephalon; Psychosis; Syntaxin; Treatment; Antipsychotic
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2009.07.029

Background Schizophrenia has been described as a disease of the synapse. On the basis of previous studies reporting reductions in the levels and activity of CK2 (also know as casein kinase 2 or II) in the brain of subjects with schizophrenia, we hypothesized that CK2-mediated phosphorylation of the presynaptic protein syntaxin 1 (Stx 1) is deficient in schizophrenia. This in turn could affect the binding of Stx 1 to its protein partners and result in abnormal neurotransmitter release and synaptic transmission. Methods We analyzed post mortem prefrontal cortex samples from 15 schizophrenia cases and matched controls by quantitative immunoblotting. Results In addition to replicating previous findings of reduced CK2 levels, we show that as predicted, the deficit in CK2 correlates with a deficit in phospho-Stx 1. In contrast, we find that these deficits are not present in depression cases. Further, we show that the reduced levels of CK2 and phospho-Stx 1 are not due to treatment with antipsychotic drugs (APDs). In fact, APDs seem to increase both CK2 and phospho-Stx 1, suggesting that their therapeutic action may be associated with the reversal of these deficits. Finally, we show that lower phospho-Stx 1 levels are associated with reduced binding of Stx 1 to SNAP-25 and MUNC18 and decreased SNARE complex formation. Conclusions Our findings constitute the first report of altered phosphorylation of a key component for neurotransmitter release in humans and suggest that regulation of Stx 1 by CK2-mediated phosphorylation could play a role in the pathophysiology of schizophrenia.