Kobori Nobuhide, Dash Pramod K
The Vivian L. Smith Center for Neurological Research, The University of Texas Medical School, Houston, Texas 77225, USA.
J Neurosci. 2006 Apr 19;26(16):4236-46. doi: 10.1523/JNEUROSCI.4687-05.2006.
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.
工作记忆(WM),即暂时将信息牢记于心的能力,对于高级认知功能至关重要,而脑损伤患者的这些高级认知功能常常受损。在这些患者中,导致工作记忆缺陷的细胞和分子机制尚不清楚,这些缺陷在没有明显损伤的情况下也可能出现。人类和猴子的背外侧前额叶皮层以及啮齿动物的内侧前额叶皮层(mPFC)的功能对工作记忆至关重要。我们证明,对大鼠进行控制性皮质撞击损伤会导致长期的工作记忆损害,这与损伤后长达1个月mPFC中γ-氨基丁酸合成酶谷氨酸脱羧酶67(GAD67)水平升高有关。在损伤后14天单次给予多巴胺D1拮抗剂足以降低GAD67水平并恢复工作记忆至少1周。这些发现表明,前额叶神经元活动的抑制导致工作记忆缺陷,并且降低GAD67表达的策略可以在脑损伤患者中提供长期的工作记忆改善。