Developmental GABAergic deficit enhances methamphetamine-induced apoptosis
Developmental GABAergic deficit enhances methamphetamine-induced apoptosis
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DOI：
10.1007/s00213-011-2269-5
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发表时间：
2011-06-01
影响因子：
3.4
通讯作者：
Koyama, Tsukasa
中科院分区：
文献类型：
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作者：
Abekawa, Tomohiro;Ito, Koki;Koyama, Tsukasa
神经解剖学证据表明 GABA 能缺陷和进行性皮质萎缩与精神分裂症一起发生。为了评估神经发育缺陷影响精神分裂症发生的神经退行性变的假设，本研究检查了一种新的动物模型，用于研究精神分裂症相关的神经发育 GABA 能缺陷在神经退行性进展中的作用。产前 N-甲基-d-天冬氨酸 (NMDA) 受体功能低下模型可诱导神经发育缺陷内侧前额叶皮质 (mPFC) 中的 GABA 能缺陷用于检查 Sprague-Dawley 大鼠的成年后代是否表现出前脉冲抑制 (PPI) 的破坏、甲基苯丙胺 (METH) (2.5 mg/kg) 诱导的 mPFC 中谷氨酸释放的增强以及该大脑区域中末端脱氧核苷酸转移酶 dUTP 缺口末端标记 (TUNEL) 阳性神经元的出现。在妊娠第 15-18 天暴露于 NMDA 受体拮抗剂 MK-801 的母鼠（MK-801 后代）表现出 mPFC 中小清蛋白免疫反应性 GABA 能中间神经元的密度降低，出生后第 63 天 (P63) 和 35 (P35) 的 PPI 破坏，以及 METH (2.5 mg/kg) 诱导的谷氨酸释放增强。重复使用这种精神兴奋剂会增加 TUNEL 阳性细胞的出现。这些发现表明，产前阻断 NMDA 受体会导致神经发育 GABA 能缺陷。 GABA 能神经元密度的降低可能与感觉运动门控 (PPI) 的破坏、METH 诱导的 mPFC 中谷氨酸释放的增强以及成年动物大脑中该区域反复注射 METH 引起的细胞凋亡增加有关。
Neuroanatomical evidence suggests that GABAergic deficits and progressive cortical atrophy occur with schizophrenia.To evaluate the hypothesis that neurodevelopmental deficits affect neurodegeneration occurring with schizophrenia, this study examined a novel animal model for schizophrenia-related neurodevelopmental GABAergic deficit in neurodegenerative progression.The prenatal N-methyl-d-aspartate (NMDA) receptor hypofunction model that induces neurodevelopmental GABAergic deficit in the medial prefrontal cortex (mPFC) was used to examine whether adult offspring of Sprague-Dawley rats exhibited disruption of prepulse inhibition (PPI), enhancement of methamphetamine (METH) (2.5 mg/kg)-induced glutamate release in the mPFC and the emergence of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive neurons in this brain region.Offspring of dams exposed to NMDA receptor antagonist MK-801 on days 15-18 of pregnancy (MK-801 offspring) showed reduced density of parvalbumin-immunoreactive GABAergic interneurons in the mPFC, PPI disruption on postnatal days 63 (P63) and 35 (P35) and an enhanced METH (2.5 mg/kg)-induced glutamate release. Repeated administration of this psychostimulant increased the emergence of TUNEL-positive cells.These findings suggest that prenatal blockade of NMDA receptors induces a neurodevelopmental GABAergic deficit. The decrease in the density of GABAergic neurons might be related to disruption of sensorimotor gating (PPI), enhanced METH-induced release of glutamate in the mPFC and a repeated METH injection-induced increase in apoptosis in this region of the brain in adult animals.