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. 2009 Nov;34(12):2601-8.
doi: 10.1038/npp.2009.90. Epub 2009 Jul 29.

Dysbindin Modulates Prefrontal Cortical Glutamatergic Circuits and Working Memory Function in Mice

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Free PMC article

Dysbindin Modulates Prefrontal Cortical Glutamatergic Circuits and Working Memory Function in Mice

James David Jentsch et al. Neuropsychopharmacology. .
Free PMC article

Abstract

Behavioral genetic studies of humans have associated variation in the DTNBP1 gene with schizophrenia and its cognitive deficit phenotypes. The protein coded for by DTNBP1, dysbindin, is expressed within forebrain glutamatergic neurons, in which it interacts with proteins involved in vesicular trafficking and exocytosis. In order to further delineate the cellular, physiological, and behavioral phenotypes associated with reduced dysbindin expression, we conducted studies in mice carrying a null mutation within the dtnbp1 gene. Dysbindin mutants showed impairments of spatial working memory compared with wild-type controls; heterozygous mice showed intermediate levels of cognitive dysfunction. Deep-layer pyramidal neurons recorded in the prefrontal cortex of mutant mice showed reductions in paired-pulse facilitation, and evoked and miniature excitatory post-synaptic currents, indicating a difference in the function of pre-synaptic glutamatergic terminals as well as elevated spike thresholds. Taken together, these data indicate that dysbindin potently regulates excitatory transmission in the prefrontal cortex, potentially through a pre-synaptic mechanism, and consequently modulates cognitive functions depending on this brain region, providing new insights into the molecular mechanisms underlying cortical dysfunction in schizophrenia.

Conflict of interest statement

Disclosure/Conflict of Interest

Dr. Jentsch has received compensation as a consultant for Merck Research Laboratories. The other author(s) declare that, except for income received from my primary employer, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

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