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The Journal of Neuroscience, April 19, 2006, 26(16):4236-4246; doi:10.1523/JNEUROSCI.4687-05.2006

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Development/Plasticity/Repair
Reversal of Brain Injury-Induced Prefrontal Glutamic Acid Decarboxylase Expression and Working Memory Deficits by D₁ Receptor Antagonism

Nobuhide Kobori^1,3 and Pramod K. Dash^1,2

¹The Vivian L. Smith Center for Neurological Research, ²Departments of Neurobiology and Anatomy and ³Neurosurgery, The University of Texas Medical School at Houston, Houston, Texas 77225

Correspondence should be addressed to P. Dash, Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, MSB 7.160, P.O. Box 20708, Houston, TX 77225. Email: p.dash{at}uth.tmc.edu

Working memory (WM), the ability to transiently hold information in mind, is essential for high-level cognitive functions that are often impaired in brain-injured patients. The cellular and molecular mechanisms contributing to WM deficits, which can manifest in the absence of overt damage, in these patients are unknown. The function of the dorsolateral prefrontal cortex in humans and monkeys, and the medial prefrontal cortex (mPFC), in rodents is critical for WM. We demonstrate that controlled cortical impact injury of rats causes a long-lasting WM impairment that is associated with increased levels of the GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) in the mPFC for up to 1 month after injury. A single administration of dopamine D₁ antagonists at 14 d after injury is sufficient to decrease GAD67 levels and restore WM for at least 1 week. These findings indicate that inhibition of prefrontal neuronal activity contributes to WM deficits and that strategies to reduce GAD67 expression can offer prolonged WM improvement in brain-injured patients.

Key words: brain injury; executive function; dorsolateral prefrontal cortex; medial prefrontal cortex; delay cells; GABAergic inhibition; D₁ antagonist

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Received Nov. 2, 2005; revised March 1, 2006; accepted March 7, 2006.

Correspondence should be addressed to P. Dash, Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, MSB 7.160, P.O. Box 20708, Houston, TX 77225. Email: p.dash{at}uth.tmc.edu

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