Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats
Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats
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DOI：
10.1007/s00213-007-0729-8
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发表时间：
2007-06-01
影响因子：
3.4
通讯作者：
Koyama, Tsukasa
中科院分区：
文献类型：
--
作者：
Abekawa, Tomohiro;Ito, Koki;Koyama, Tsukasa
小清蛋白的神经发育缺陷已报道精神分裂症患者前额叶皮层中的氨基丁酸（GABA）能中间神经元。谷氨酸通过N-甲基-D-天冬氨酸（NMDA）受体介导的机制影响这种类型的中间神经元的增殖。本研究假设，产前阻断NMDA受体会破坏GABA能神经发育，导致对非竞争性NMDA拮抗剂苯环己哌啶（PCP）和多巴胺受体拮抗剂甲基苯丙胺（METH）的行为反应的影响差异。方法用小白蛋白抗体对GABA能神经元进行免疫组化染色。使用红外传感器测量精神兴奋剂诱导的过度运动。结果NMDA受体拮抗剂MK-801可降低出生后63天大鼠内侧前额叶皮质（P63）内小核白蛋白免疫反应神经元的密度，增强PCP诱导的过度运动，但不影响METH对P63的急性效应或行为敏感化的发展。出生前暴露于MK-801甚至在出生后第35天（P35）减少了小白蛋白免疫反应神经元的数量，并且没有增强PCP诱导的过度运动、METH对P35的急性效应或对METH的行为敏感化的发展。结论产前阻断NMDA受体可阻断内侧前额叶皮层GABA能神经元的发育，这种阻断可能与PCP对青春期后子代而非幼年子代的运动诱导作用增强有关。GABA能缺乏与METH的作用无关。产前暴露于MK-801的成年后代中的这种GABA能神经发育中断和增强的PCP诱导的过度运动可能被证明可作为通过NMDA受体介导的脑功能减退机制的难治性精神分裂症发病机制的神经发育过程的新模型。
Rationale Neurodevelopmental deficits of parvalbuminimmunoreactive.- aminobutyric acid (GABA) ergic interneurons in prefrontal cortex have been reported in schizophrenia. Glutamate influences the proliferation of this type of interneuron by an N-methyl-D-aspartate (NMDA)-receptor-mediated mechanism. The present study hypothesized that prenatal blockade of NMDA receptors would disrupt GABAergic neurodevelopment, resulting in differences in effects on behavioral responses to a noncompetitive NMDA antagonist, phencyclidine (PCP), and a dopamine releaser, methamphetamine (METH). Methods GABAergic neurons were immunohistochemically stained with parvalbumin antibody. Psychostimulant-induced hyperlocomotion was measured using an infrared sensor. Results Prenatal exposure (E15-E18) to the NMDA receptor antagonist MK-801 reduced the density of parvalbuminimmunoreactive neurons in rat medial prefrontal cortex on postnatal day 63 (P63) and enhanced PCP-induced hyperlocomotion but not the acute effects of METH on P63 or the development of behavioral sensitization. Prenatal exposure to MK-801 reduced the number of parvalbuminimmunoreactive neurons even on postnatal day 35 (P35) and did not enhance PCP- induced hyperlocomotion, the acute effects of METH on P35, or the development of behavioral sensitization to METH. Conclusions These findings suggest that prenatal blockade of NMDA receptors disrupts GABAergic neurodevelopment in medial prefrontal cortex, and that this disruption of GABAergic development may be related to the enhancement of the locomotion-inducing effect of PCP in postpubertal but not juvenile offspring. GABAergic deficit is unrelated to the effects of METH. This GABAergic neurodevelopmental disruption and the enhanced PCP-induced hyperlocomotion in adult offspring prenatally exposed to MK-801 may prove useful as a new model of the neurodevelopmental process of pathogenesis of treatment-resistant schizophrenia via an NMDA-receptor-mediated hypoglutamatergic mechanism.