Reversal of Brain Injury-Induced Prefrontal Glutamic Acid Decarboxylase Expression and Working Memory Deficits by D₁Receptor Antagonism

Abstract

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 D 1 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.

Delayed increase of tyrosine hydroxylase expression in rat nigrostriatal system after traumatic brain injury

“…While experimental TBI can alter elements of the ubiquitin-proteasome pathway (Lotocki et al, 2003;Williams et al, 2006;Yao et al, 2006), it is unknown if this is sufficient to prevent TH degradation. Another possibility is that a post-translational modification may render TH less sensitive to degradation or alter its activity via phosphorylation (Kobori and Dash, 2006). Lastly, while it is possible that tissue shrinkage may affect TH protein, this appeared unlikely in the present study given that a greater increase in TH expression was detected in the contralateral striatum, which had no tissue loss relative to the ipsilateral striatum.…”

“…Our previous report confirms the clinical observation that delayed and chronic treatment with the D2 receptor agonist bromocriptine attenuates both working memory and spatial learning acquisition deficits following TBI insult in rats . Recently, Kobori and Dash (2006) demonstrate that experimental TBI produces a long-lasting working memory impairment that is associated with increased levels of the GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) in the medial prefrontal cortex for up to 1 month after injury. A single administration of dopamine D 1 antagonists at 14 d after injury is sufficient to decrease GAD67 levels and restore working memory (Kobori and Dash, 2006).…”

“…Recently, Kobori and Dash (2006) demonstrate that experimental TBI produces a long-lasting working memory impairment that is associated with increased levels of the GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) in the medial prefrontal cortex for up to 1 month after injury. A single administration of dopamine D 1 antagonists at 14 d after injury is sufficient to decrease GAD67 levels and restore working memory (Kobori and Dash, 2006). The present data demonstrates an associative, but not causal relationship between TH up-regulation and behavioral dysfunction after TBI.…”

Hypothermia alleviates hypoxic ischemia-induced dopamine dysfunction and memory impairment in rats

“…Ischemic injury in gerbils impaired memory and increased apoptotic neuronal cell death in the hippocampal CA1 region (Ko et al 2009). Cortical impact injury in rats caused long-lasting working memory impairment (Kobori and Dash 2006). Traumatic brain injury (TBI) also increased latency in the step-down avoidance task with increasing apoptosis in the hippocampus, showing that injury to the hippocampus induced impairment of performance (Kim et al 2010a).…”

Restoration of Neuroendocrine Stress Response by Glucocorticoid Receptor or GABAAReceptor Antagonists after Experimental Traumatic Brain Injury

“…Thus, restoration of the stressinduced CORT response with BIC indicates that CCI may have impacted GABAergic PVN projecting neurons from upstream limbic or cortical regions that are stress responsive and regulate the HPA axis-e.g., ventral subiculum, medial prefrontal cortex, amgydaloid nuclei, and lateral septum. 16 Whereas GAD-67 levels have been shown to be increased within the medial prefrontal cortex from 1 to 28 days post-injury 30 and to return to control levels by 4 months post-CCI, 31 our current results for PV-and GAD-67-positive cells in the regions of the prefrontal cortex, showing no effects at 57-59 days after moderate CCI, indicate that changes in numbers of inhibitory cells within Cg1, PrL, or IL are not likely to explain the altered HPA axis responses seen after TBI.…”