Toriumi Kazuya, Oki Mika, Muto Eriko, Tanaka Junko, Mouri Akihiro, Mamiya Takayoshi, Kim Hyoung-Chun, Nabeshima Toshitaka
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
Project for Schizophrenia Research, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Psychopharmacology (Berl). 2016 Jun;233(12):2373-81. doi: 10.1007/s00213-016-4288-8. Epub 2016 Apr 20.
We previously reported that prenatal treatment with phencyclidine (PCP) induces glutamatergic dysfunction in the prefrontal cortex (PFC), leading to schizophrenia-like behavioral deficits in adult mice. However, little is known about the prenatal effect of PCP treatment on other types of neurons.
We focused on γ-aminobutyric acid (GABA)-ergic interneurons and evaluated the effect of prenatal PCP exposure on the neurodevelopment of GABAergic interneurons in the PFC.
PCP was administered at the dose of 10 mg/kg/day to pregnant dams from embryonic day 6.5 to 18.5. After the pups were reared to adult, we analyzed their GABAergic system in the PFC using immunohistological, biochemical, and behavioral analyses in adulthood.
The prenatal PCP treatment decreased the density of parvalbumin-positive cells and reduced the expression level of glutamic acid decarboxylase 67 (GAD67) and GABA content of the PFC in adults. Additionally, prenatal PCP treatment induced behavioral deficits in adult mice, such as hypersensitivity to PCP and prepulse inhibition (PPI) deficits. These behavioral deficits were ameliorated by pretreatment with the GABAB receptor agonist baclofen. Furthermore, the density of c-Fos-positive cells was decreased after the PPI test in the PFC of mice treated with PCP prenatally, and this effect was ameliorated by pretreatment with baclofen.
These findings suggest that prenatal treatment with PCP induced GABAergic dysfunction in the PFC, which caused behavioral deficits.
我们之前报道过，孕期给予苯环利定（PCP）会导致前额叶皮质（PFC）谷氨酸能功能障碍，进而在成年小鼠中引发类似精神分裂症的行为缺陷。然而，关于PCP孕期治疗对其他类型神经元的影响却知之甚少。
我们聚焦于γ-氨基丁酸（GABA）能中间神经元，评估孕期暴露于PCP对PFC中GABA能中间神经元神经发育的影响。
从胚胎第6.5天至18.5天，以10mg/kg/天的剂量给怀孕母鼠注射PCP。幼崽饲养至成年后，我们在成年期使用免疫组织学、生物化学和行为学分析方法，对其PFC中的GABA能系统进行分析。
孕期PCP治疗降低了小白蛋白阳性细胞的密度，降低了成年小鼠PFC中谷氨酸脱羧酶67（GAD67）的表达水平以及GABA含量。此外，孕期PCP治疗导致成年小鼠出现行为缺陷，如对PCP过敏和前脉冲抑制（PPI）缺陷。GABAB受体激动剂巴氯芬预处理可改善这些行为缺陷。此外，在孕期接受PCP治疗的小鼠的PFC中，PPI测试后c-Fos阳性细胞的密度降低，而巴氯芬预处理可改善这一效应。
这些发现表明，孕期PCP治疗会导致PFC中GABA能功能障碍，进而引起行为缺陷。
