Document Detail


Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance.
MedLine Citation:
PMID:  21035792     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Schizophrenia is a heritable disorder associated with disrupted neural transmission and dysfunction of brain systems involved in higher cognition. The gene encoding dystrobrevin-binding-protein-1 (dysbindin) is a putative candidate gene associated with cognitive impairments, including memory deficits, in both schizophrenia patients and unaffected individuals. The underlying mechanism is thought to be based in changes in glutamatergic and dopaminergic function within the corticostriatal networks known to be critical for schizophrenia. This hypothesis derives support from studies of mice with a null mutation in the dysbindin gene that exhibit memory dysfunction and excitatory neurotransmission abnormalities in prefrontal and hippocampal networks. At a cellular level, dysbindin is thought to mediate presynaptic glutamatergic transmission.
METHODS: We investigated the relationship between glutamate receptor dynamics and memory performance in dysbindin mutant mice. We assessed N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor function in prefrontal cortex pyramidal neurons in vitro with whole-cell recordings, molecular quantitative analyses (reverse transcription-polymerase chain reaction) of the mandatory NMDA receptor subunit NR1, and cognitive function with a spatial working memory task.
RESULTS: Decreases in dysbindin are associated with specific decreases in NMDA-evoked currents in prefrontal pyramidal neurons, as well as decreases in NR1 expression. Furthermore, the degree of NR1 expression correlates with spatial working memory performance, providing a mechanistic explanation for cognitive changes previously associated with dysbindin expression.
CONCLUSIONS: These data show a significant downregulation of NMDA receptors due to dysbindin deficiency and illuminate molecular mechanisms mediating the association between dysbindin insufficiency and cognitive impairments associated with schizophrenia, encouraging study of the dysbindin/NR1 expression association in humans with schizophrenia.
Authors:
Katherine H Karlsgodt; Karla Robleto; Heather Trantham-Davidson; Corey Jairl; Tyrone D Cannon; Antonieta Lavin; J David Jentsch
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-10-30
Journal Detail:
Title:  Biological psychiatry     Volume:  69     ISSN:  1873-2402     ISO Abbreviation:  Biol. Psychiatry     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-14     Completed Date:  2011-06-20     Revised Date:  2014-10-21    
Medline Journal Info:
Nlm Unique ID:  0213264     Medline TA:  Biol Psychiatry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  28-34     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Carrier Proteins / biosynthesis*,  genetics
Down-Regulation / genetics
Female
Male
Memory, Short-Term / physiology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Patch-Clamp Techniques / methods
Prefrontal Cortex / metabolism,  physiology
Pyramidal Cells / physiology
Receptors, AMPA / physiology
Receptors, N-Methyl-D-Aspartate / biosynthesis,  physiology*
Grant Support
ID/Acronym/Agency:
K12 GM081265/GM/NIGMS NIH HHS; K12-GM081265/GM/NIGMS NIH HHS; MH-83269/MH/NIMH NIH HHS; P1-NS062410/NS/NINDS NIH HHS; RL1 MH083269/MH/NIMH NIH HHS; RL1 MH083270/MH/NIMH NIH HHS; T32 NS048004/NS/NINDS NIH HHS; T32-NS048004:03/NS/NINDS NIH HHS; UL1 DE019580/DE/NIDCR NIH HHS; UL1 RR024911/RR/NCRR NIH HHS; UL1-DE19580/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/Dtnbp1 protein, mouse; 0/NR1 NMDA receptor; 0/Receptors, AMPA; 0/Receptors, N-Methyl-D-Aspartate
Comments/Corrections
Comment In:
Biol Psychiatry. 2011 Jan 1;69(1):2-4   [PMID:  21145442 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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