Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance.

Abstract

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
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 69 Issue 1 Pg. 28-34 (Jan 01 2011) ISSN: 1873-2402 [Electronic] United States
• PMID: 21035792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• Dtnbp1 protein, mouse
• Dysbindin
• Dystrophin-Associated Proteins
• NR1 NMDA receptor
• Receptors, AMPA
• Receptors, N-Methyl-D-Aspartate

Topics

• Animals
• Carrier Proteins (biosynthesis, genetics)
• Down-Regulation (genetics)
• Dysbindin
• Dystrophin-Associated Proteins
• 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)