Deficits in syntaxin 1 phosphorylation in schizophrenia prefrontal cortex.

Abstract

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.

• Authors: Max A Castillo, Subroto Ghose, Carol A Tamminga, Paula G Ulery-Reynolds
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 67 Issue 3 Pg. 208-16 (Feb 01 2010) ISSN: 1873-2402 [Electronic] United States
• PMID: 19748077 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antipsychotic Agents
• NR1 NMDA receptor
• Phosphoproteins
• RNA-Binding Proteins
• Receptors, N-Methyl-D-Aspartate
• SNARE Proteins
• Syntaxin 1
• nucleolin
• Casein Kinase II
• Phosphoric Monoester Hydrolases

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antipsychotic Agents (pharmacology)
• Casein Kinase II (metabolism)
• Cohort Studies
• Female
• Gene Expression Regulation (physiology)
• Humans
• Immunoprecipitation (methods)
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Phosphoproteins (metabolism)
• Phosphoric Monoester Hydrolases (pharmacology)
• Phosphorylation
• Postmortem Changes
• Prefrontal Cortex (drug effects, metabolism)
• RNA-Binding Proteins (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (metabolism)
• SNARE Proteins (metabolism)
• Schizophrenia (pathology)
• Syntaxin 1 (metabolism)
• Time Factors
• Young Adult