Chronic desipramine treatment rescues depression-related, social and cognitive deficits in Engrailed-2 knockout mice.
Chronic desipramine treatment rescues depression-related, social and cognitive deficits in Engrailed-2 knockout mice.
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DOI：
10.1111/gbb.12115
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Crawley JN
中科院分区：
文献类型：
--
作者：
Brielmaier J;Senerth JM;Silverman JL;Matteson PG;Millonig JH;DiCicco-Bloom E;Crawley JN
Engrailed-2（En 2）是一种同源框转录因子，调节神经发育过程，包括神经元连接和腹侧后脑单胺能神经元的发育。我们先前报道了En 2无效突变小鼠大脑去甲肾上腺素能浓度异常，伴随着强迫游泳试验中不动性增加，与抑郁症相关。EN 2基因多态性与自闭症谱系障碍（ASD）相关，并且具有En 2缺失的小鼠显示可能与多种神经精神疾病相关的社交异常和认知缺陷。本研究评估了地昔帕明（DMI）（一种选择性去甲肾上腺素再吸收抑制剂和经典抗抑郁药）长期治疗逆转En 2-/-小鼠行为异常的能力。在尾悬挂和强迫游泳测试中，E2处理显著降低了不动性，恢复了三室社交方法任务中的社交能力，并逆转了En 2 −/−小鼠的情境恐惧条件反射损伤。我们的研究结果表明，大脑去甲肾上腺素能系统的调节拯救了En 2 −/−小鼠的抑郁相关表型，并表明去甲肾上腺素在神经精神疾病（如自闭症或精神分裂症）中的社会和认知缺陷的病理生理学中的新作用。
Engrailed-2 (En2) is a homeobox transcription factor that regulates neurodevelopmental processes including neuronal connectivity and elaboration of monoaminergic neurons in the ventral hindbrain. We previously reported abnormalities in brain noradrenergic concentrations in En2 null mutant mice that were accompanied by increased immobility in the forced swim test, relevant to depression. An EN2 genetic polymorphism has been associated with autism spectrum disorders (ASD), and mice with a deletion in En2 display social abnormalities and cognitive deficits that may be relevant to multiple neuropsychiatric conditions. The present study evaluated the ability of chronic treatment with desipramine (DMI), a selective norepinephrine reuptake inhibitor and classical antidepressant, to reverse behavioral abnormalities in En2 −/− mice. DMI treatment significantly reduced immobility in the tail suspension and forced swim tests, restored sociability in the three-chambered social approach task, and reversed impairments in contextual fear conditioning in En2 −/− mice. Our findings indicate that modulation of brain noradrenergic systems rescues the depression-related phenotype in En2 −/− mice and suggest new roles for norepinephrine in the pathophysiology of the social and cognitive deficits seen in neuropsychiatric disorders such as autism or schizophrenia.
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