Andrews Jessica L, Newell Kelly A, Matosin Natalie, Huang Xu-Feng, Fernandez-Enright Francesca
Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522 Australia; Schizophrenia Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010 Australia.
Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522 Australia; Schizophrenia Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010 Australia; School of Psychology, Faculty of Social Sciences, University of Wollongong, Wollongong, New South Wales 2522 Australia.
Prog Neuropsychopharmacol Biol Psychiatry. 2015 Dec 3;63:91-7. doi: 10.1016/j.pnpbp.2015.06.003. Epub 2015 Jun 10.
Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that components of the Lingo-1 signaling pathways may be involved in the acute neurotoxicity induced by perinatal administration of PCP in rats early in development and suggest that this may have implications for the hippocampal deficits seen in schizophrenia.
在啮齿动物出生后给予苯环己哌啶（PCP）会对神经过程造成重大干扰，导致成年后正常行为特征发生严重改变。它通常被用于模拟精神疾病，如精神分裂症，会引发该毁灭性疾病中存在的许多大脑功能失调过程，包括神经发育过程中细胞凋亡水平升高以及髓鞘形成和可塑性过程受到破坏。富含亮氨酸重复序列和免疫球蛋白结构域蛋白1（Lingo-1）负责负向调节神经突生长和轴突髓鞘形成。最近使用死后人类大脑队列的研究结果表明，Lingo-1在Nogo受体（NgR）/p75/肿瘤坏死因子受体孤儿Y（TROY）信号复合物中的信号传导伙伴，以及下游信号传导伙伴无赖氨酸（K）激酶1（WNK1）和髓鞘转录因子1（Myt1），在精神分裂症病理生理学中起重要作用。在此，我们研究了Lingo-1及其信号传导伙伴在使用PCP建立的精神分裂症神经发育模型中的作用，以确定这些通路在神经发育的不同阶段是否在海马体中发生改变。雄性斯普拉格-道利大鼠在出生后第7、9和11天皮下注射PCP（10mg/kg）或生理盐水。大鼠（每组n = 6）在出生后第12天、5周或14周处死。检测处理后大鼠海马体中Lingo-1信号蛋白的相对表达水平。在出生后第12天，PCP处理组大鼠的p75和Myt1水平降低（0.001≤p≤0.011）。在5周时，所有检测蛋白均无显著变化（p>0.05）。在14周时，PCP处理组大鼠的p75、TROY和Myt1水平升高（0.014≤p≤0.022）。这是关于大鼠海马体中Lingo-1信号蛋白在发育早期PCP处理后及成年期发生改变的首次报道。基于我们的研究结果，我们提出Lingo-1信号通路的组成部分可能参与围产期给予PCP诱导的大鼠早期发育急性神经毒性作用，并表明这可能与精神分裂症中所见的海马体缺陷有关。
