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Bdnf deficiency in the neonatal hippocampus contributes to global dna hypomethylation and adult behavioral changes
Brain Research ( IF 2.7 ) Pub Date : 2021-01-07 , DOI: 10.1016/j.brainres.2020.147254
Daniel A Paredes 1 , Ahmad Jalloh 2 , Briony J Catlow 3 , Amritha Jaishankar 4 , Seungmae Seo 5 , Dennisse V Jimenez 6 , Keri Martinowich 4 , Marcelo Diaz-Bustamante 7 , Daniel J Hoeppner 4 , Ronald D G McKay 6
Affiliation  

Schizophrenia is a neurodevelopmental psychiatric disorder, encompassing genetic and environmental risk factors. For several decades, investigators have been implementing the use of lesions of the neonatal rodent hippocampus to model schizophrenia, resulting in a broad spectrum of adult schizophrenia-related behavioral changes. Despite the extensive use of these proposed animal models of schizophrenia, the mechanisms by which these lesions result in schizophrenia-like behavioral alterations remain unclear. Here we provide in vivo evidence that transient pharmacological inactivation of the hippocampus via tetrodotoxin microinjections or a genetic reduction in brain derived neurotrophic factor (BDNF) protein levels (BDNF+/- rats) lead to global DNA hypomethylation, disrupted maturation of the neuronal nucleus and aberrant acoustic startle response in the adult rat. The similarity between the effects of the two treatments strongly indicate that BDNF signaling is involved in effects obtained after the TTX microinjections. These findings may shed light on the cellular mechanisms underlying the phenotypical features of neonatal transient inhibition of the hippocampus as a preclinical model of schizophrenia and suggest that BDNF signaling represents a target pathway for development of novel treatment therapies.



中文翻译:

新生儿海马 Bdnf 缺乏导致整体 dna 低甲基化和成人行为改变

精神分裂症是一种神经发育性精神障碍,包括遗传和环境危险因素。几十年来,研究人员一直在实施使用新生啮齿动物海马体的损伤来模拟精神分裂症,从而导致广泛的成人精神分裂症相关行为变化。尽管这些提议的精神分裂症动物模型被广泛使用,但这些病变导致精神分裂症样行为改变的机制仍不清楚。在这里,我们提供了体内证据,表明通过河豚毒素显微注射或脑源性神经营养因子 (BDNF) 蛋白水平 (BDNF +/-大鼠)导致整体 DNA 低甲基化、神经元核成熟中断和成年大鼠的异常声学惊吓反应。两种治疗效果之间的相似性强烈表明 BDNF 信号与 TTX 显微注射后获得的效果有关。这些发现可能揭示了作为精神分裂症临床前模型的新生儿瞬时海马体抑制表型特征背后的细胞机制,并表明 BDNF 信号传导代表了开发新型治疗疗法的目标途径。

更新日期:2021-01-07
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