The influence of NMDA and GABA(A) receptors and glutamic acid decarboxylase (GAD) activity on attention.
The influence of NMDA and GABA(A) receptors and glutamic acid decarboxylase (GAD) activity on attention.
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DOI：
10.1007/s00213-012-2792-z
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发表时间：
2013-01
影响因子：
3.4
通讯作者：
Moghaddam, Bita
中科院分区：
文献类型：
--
作者：
Pehrson, Alan L.;Bondi, Corina O.;Totah, Nelson K. B.;Moghaddam, Bita
注意力功能障碍是与包括精神分裂症在内的主要精神疾病相关的认知缺陷的标志。精神分裂症的认知缺陷归因于 N-甲基-D-天冬氨酸 (NMDA) 受体功能降低或γ-氨基丁酸 (GABA) 合成酶谷氨酸脱羧酶-67 表达减少，这可能导致 GABAA 受体的神经传递减弱。本研究使用啮齿动物模型来比较 NMDA 和 GABAA 受体的抑制以及 GAD 活性对注意力的影响。我们测试了在全脑或前扣带皮层（ACC）中抑制这些蛋白质的影响，前扣带皮层是对注意力处理至关重要的前额叶皮层区域。老鼠接受了三选择串行反应时间任务（3-CSRT）的训练，这是一种注意力测试。在训练有素的大鼠中测量全身或 ACC 内注射药物对性能的影响。使用直接拮抗剂 SR95531（1 或 3 ng/侧）或全身注射苯二氮卓反向激动剂 FG7142（5 mg/kg）降低 ACC 内的 GABAA 受体功能，会降低准确性并增加遗漏。使用 MK-801（分别为 3 mg/kg 或 3 μg）对 NMDA 受体进行全身或 ACC 内抑制也会损害性能。当全身或在 ACC 内给药时，用 3-巯基丙酸抑制 GAD，即使在高剂量下，也不会对 3-CSRT 准确性或遗漏产生影响。这些数据表明，虽然 ACC 内 NMDA 和 GABAA 受体的强直刺激对于注意力表现至关重要，但 GAD 活性的减少可能没有什么功能意义，并且并不表示 GABA 神经传递减少。
Attention dysfunction is the hallmark of cognitive deficits associated with major psychiatric illnesses including schizophrenia. Cognitive deficits of schizophrenia have been attributed to reduced function of the N-methyl-D-aspartate (NMDA) receptor or reduced expression of the gamma-aminobutyric acid (GABA)-synthesizing enzyme glutamic acid decarboxylase-67, which presumably leads to attenuated neurotransmission at GABAA receptors. The present study used a rodent model to compare the inhibition of NMDA and GABAA receptors, and GAD activity on attention. We tested the impact of inhibiting these proteins brain wide or in the anterior cingulate cortex (ACC), a prefrontal cortex region critical for attentional processing. Rats were trained on the three choice serial reaction time task (3-CSRT), an attention test. The impact of systemic or intra-ACC injection of drugs on performance was measured in well-trained rats. Reducing GABAA receptor function within the ACC with the direct antagonist SR95531 (1 or 3 ng/side) or brain wide using systemic injection of the benzodiazepine inverse agonist FG7142 (5 mg/kg) impaired accuracy and increased omissions. Systemic or intra-ACC inhibition of NMDA receptors using MK-801 (at 3 mg/kg or 3 μg, respectively) also impaired performance. Inhibition of GAD with 3-mercaptopropionic acid, even at high doses, had no effect on 3-CSRT accuracy or omissions when administered systemically or within the ACC. These data demonstrate that, while tonic stimulation of NMDA and GABAA receptors within the ACC are critical for attentional performance, reduction in GAD activity may have little functional significance and is not indicative of reduced GABA neurotransmission.
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