Reversal of brain injury-induced prefrontal glutamic acid decarboxylase expression and working memory deficits by D1 receptor antagonism.
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.
Kobori
Nobuhide
N
The Vivian L. Smith Center for Neurological Research, The University of Texas Medical School, Houston, Texas 77225, USA.
Dash
Pramod K
PK
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000201:enzymology*; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D018756:GABA Antagonists / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000096:biosynthesis*; D007527:Isoenzymes / Q000096:biosynthesis; D008569:Memory Disorders / Q000188:drug therapy / Q000201:enzymology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018492:Dopamine Antagonists; D018756:GABA Antagonists; D007527:Isoenzymes; D017447:Receptors, Dopamine D1; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1