Zhejiang Key Laboratory of Pathophysiology, Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd, Ningbo, Zhejiang 315211, China; Key Laboratory of Addiction Research of Zhejiang Province, Ningbo Kangning Hospital, Ningbo, Zhejiang 315010, China; State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin, China.
Zhejiang Key Laboratory of Pathophysiology, Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd, Ningbo, Zhejiang 315211, China.
Pharmacol Biochem Behav. 2021 Mar;202:173103. doi: 10.1016/j.pbb.2021.173103. Epub 2021 Jan 12.
Neurodevelopmental abnormalities are associated with cognitive dysfunction in schizophrenia. In particular, deficits of working memory, are consistently observed in schizophrenia, reflecting prefrontal cortex (PFc) dysfunction. To elucidate the mechanism of such deficits in working memory, the pathophysiological properties of PFc neurons and synaptic transmission have been studied in several developmental models of schizophrenia. Given the pathogenetic heterogeneity of schizophrenia, comparison of PFc synaptic transmission between models of prenatal and postnatal defect would promote our understanding on the developmental components of the biological vulnerability to schizophrenia. In the present study, we investigated the excitatory synaptic transmission onto pyramidal cells localized in layer 5 of the medial PFc (mPFc) in two developmental models of schizophrenia: gestational methylazoxymethanol acetate (MAM) administration and post-weaning social isolation (SI). We found that both models exhibited defective spatial working memory, as indicated by lower spontaneous alternations in a Y-maze paradigm. The recordings from pyramidal neurons in both models exhibited decreased spontaneous excitatory postsynaptic current (sEPSC), representing the reduction of excitatory synaptic transmission in the mPFc. Interestingly, a positive correlation between the impaired spontaneous alternation behavior and the decreased excitatory synaptic transmission of pyramidal neurons was found in both models. These findings suggest that diminished excitatory neurotransmission in the mPFc could be a common pathophysiology regardless of the prenatal and postnatal pathogenesis in developmental models of schizophrenia, and that it might underlie the mechanism of defective working memory in those models.
神经发育异常与精神分裂症的认知功能障碍有关。特别是，工作记忆缺陷在精神分裂症中经常被观察到，反映了前额叶皮层（PFc）的功能障碍。为了阐明工作记忆缺陷的机制，已经在几种精神分裂症的发育模型中研究了 PFc 神经元和突触传递的病理生理特性。鉴于精神分裂症的发病机制异质性，比较产前和产后缺陷模型中的 PFc 突触传递将促进我们对精神分裂症生物易感性的发育成分的理解。在本研究中，我们研究了两种精神分裂症发育模型中的内侧 PFc（mPFc）中第 5 层锥体神经元的兴奋性突触传递：妊娠期甲基偶氮甲烷乙酸盐（MAM）给药和断奶后社交隔离（SI）。我们发现这两种模型都表现出空间工作记忆缺陷，表现在 Y 型迷宫范式中的自发交替减少。两种模型中的锥体神经元记录到自发兴奋性突触后电流（sEPSC）减少，代表 mPFc 中的兴奋性突触传递减少。有趣的是，在两种模型中都发现受损的自发交替行为与锥体神经元兴奋性突触传递减少之间存在正相关。这些发现表明，mPFc 中兴奋性神经递质传递的减少可能是精神分裂症发育模型中无论产前还是产后发病机制都存在的共同病理生理学，并且可能是这些模型中工作记忆缺陷的机制。
