Selective reorganization of GABAergic transmission in neonatal ventral hippocampal-lesioned rats
Selective reorganization of GABAergic transmission in neonatal ventral hippocampal-lesioned rats
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DOI：
10.1017/s1461145709009985
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发表时间：
2009-09-01
影响因子：
4.8
通讯作者：
Nehlig, Astrid
中科院分区：
文献类型：
--
作者：
Francois, Jennifer;Ferrandon, Arielle;Nehlig, Astrid
尸检研究表明，精神分裂症患者的 GABA 能系统受到干扰。新生腹侧海马损伤（NVHL）大鼠被用作精神分裂症的神经发育模型。在这里，我们对 GABA 能系统进行了表征，重点关注 GABA 合成酶 GAD67、GABA 能中间神经元特征蛋白和 GABA 转运蛋白 gat-1。由于 GABA 能系统对大脑兴奋性至关重要，因此还在此类大鼠中评估了对 GABA(A) 受体拮抗剂戊四氮 (PTZ) 给药的敏感性。雄性幼犬在出生后第 7 天用鹅膏菌酸进行损伤。成年后，对它们进行标准行为测试，即惊吓反射的前脉冲抑制和阿扑吗啡下增加的运动，以评估损伤和 PTZ 输注测试的有效性，然后对 GABA 能神经元标记进行免疫组织化学检查。我们发现负责 GABA 合成的酶 GAD67 存在广泛的扰动，并且特定中间神经元减少，仅限于海马、内嗅和前额皮质，但 gat-l 阳性纤维没有改变。该模型的常见行为特性，例如阿扑吗啡下的过度运动和感觉运动门控的缺陷得到了证实。 NVHL 大鼠表现出皮质兴奋性的变化，反映为比假手术大鼠对尖波放电的敏感性更高，并且通过增加 PTZ 剂量诱导阵挛性癫痫发作的敏感性降低。这些发现表明，新生儿腹侧海马体损伤会引起 GABA 能系统的改变，从而对大脑兴奋性产生功能性影响，这为 GABA 能系统可能参与精神分裂症的病理生理学这一观点提供了支持。
Post-mortem studies suggested a disturbance of the GABAergic system in schizophrenia. Neonatal ventral hippocampal-lesioned (NVHL) rats were used as a neurodevelopmental model of schizophrenia. Here, we characterized the GABAergic system, focusing on the GABA-synthesizing enzyme, GAD67, GABAergic interneuron characteristic proteins, and the GABA transporter, gat-1. As the GABAergic system is crucial to brain excitability, the sensitivity to pentylenetetrazol (PTZ) administration, an antagonist of GABA(A) receptors, was also evaluated in such rats. Male pups were lesioned with ibotenic acid at postnatal day 7. As adults, they were submitted to standard behavioural tests, i.e. prepulse inhibition of the startle reflex and increased locomotion under apomorphine, to assess the effectiveness of the lesions and the PTZ infusion test before immunohistochemistry of the GABAergic neuron markers. We found a widespread perturbation of the enzyme responsible for GABA synthesis, GAD67 and a decrease of specific interneurons, restricted to the hippocampus, entorhinal and prefrontal cortex, but no alteration of gat-l-positive fibres. The usual behavioural properties of the model, such as hyperlocomotion under apomorphine and a deficit in sensorimotor gating were confirmed. NVHL rats showed changes in cortical excitability reflected by higher susceptibility than sham-operated rats to spike wave discharges and decreased susceptibility to clonic seizures, induced by increasing the dose of PTZ. These findings indicate that a neonatal lesion of the ventral hippocampus elicits alterations in the GABAergic system leading to functional consequences on brain excitability, lending support to the idea that GABAergic systems could be involved in the pathophysiology of schizophrenia.