Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in Angelman syndrome model mice by ErbB inhibitors.
Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in Angelman syndrome model mice by ErbB inhibitors.
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DOI：
10.1016/j.biopsych.2012.01.021
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发表时间：
2012-08-01
影响因子：
10.6
通讯作者：
Klann, Eric
中科院分区：
文献类型：
--
作者：
Kaphzan, Hanoch;Hernandez, Pepe;Jung, Joo In;Cowansage, Kiriana K.;Deinhardt, Katrin;Chao, Moses V.;Abel, Ted;Klann, Eric
安杰曼综合征(AS)是一种与自闭症、智力低下、运动异常和癫痫有关的人类神经精神障碍。在大多数情况下，AS是由于编码泛素连接酶E3A的UBE3A基因母体拷贝缺失引起的，也称为E6-AP。已经产生了一种AS的小鼠模型，这些小鼠表现出许多在人类身上观察到的神经变化。由于AS和精神分裂症的临床和神经解剖学相似，我们研究了AS模型小鼠神经调节蛋白-ErbB4通路的变化，该通路与精神分裂症的病理生理学有关。我们的研究重点是海马体，这是AS小鼠受损的主要大脑部位之一。我们检测了AS小鼠和野生型(10-16周龄)仔鼠NRG1和ErbB4受体的表达，并研究了ErbB抑制对海马区CA1区长时程增强(LTP)和海马区依赖情景恐惧记忆的影响。我们观察到AS模型小鼠海马区NeuRegin-ErbB4信号的增强，发现ErbB抑制剂可以逆转LTP的缺陷，LTP是学习和记忆的细胞底物。此外，我们发现ErbB抑制剂增强了AS模型小鼠的长期背景恐惧记忆。我们的研究结果表明，NeuRegin-ErbB4信号通路参与了AS模型小鼠的突触可塑性和记忆障碍，提示ErbB抑制剂具有治疗AS的潜力。
Angelman syndrome (AS) is a human neuropsychiatric disorder associated with autism, mental retardation, motor abnormalities, and epilepsy. In most cases, AS is caused by the deletion of the maternal copy of UBE3A gene, which encodes the enzyme ubiquitin ligase E3A, also termed E6-AP. A mouse model of AS has been generated and these mice exhibit many of the observed neurological alterations in humans. Because of clinical and neuroanatomical similarities between AS and schizophrenia, we examined AS model mice for alterations in the neuregulin-ErbB4 pathway, which has been implicated in the pathophysiology of schizophrenia. We focused our studies on the hippocampus, one of the major brain loci impaired in AS mice. We determined the expression of NRG1 and ErbB4 receptors in AS mice and wild-type littermates (ages 10-16 weeks), and studied the effects of ErbB inhibition on long-term potentiation (LTP) in hippocampal area CA1 and on hippocampus-dependent contextual fear memory. We observed enhanced neuregulin-ErbB4 signaling in the hippocampus of AS model mice and found that ErbB inhibitors could reverse deficits in LTP, a cellular substrate for learning and memory. In addition, we found that an ErbB inhibitor enhanced long-term contextual fear memory in AS model mice. Our findings suggest that neuregulin-ErbB4 signaling is involved in synaptic plasticity and memory impairments in AS model mice, suggesting that ErbB inhibitors have therapeutic potential for the treatment of AS.
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影响因子：
16.2
作者：
Huang, YZ;Won, S;Mei, L
通讯作者：
Mei, L
影响因子：
56.9
作者：
HOLMES, WE;SLIWKOWSKI, MX;VANDLEN, RL
通讯作者：
VANDLEN, RL
DOI：
10.1073/pnas.1010669107
发表时间：
2010-12-14
影响因子：
11.1
作者：
Chen, Yong-Jun;Zhang, Meng;Gao, Tian-Ming
通讯作者：
Gao, Tian-Ming
影响因子：
15.9
作者：
Hoeffer, Charles A.;Klann, Eric
通讯作者：
Klann, Eric
影响因子：
2.5
作者：
Gerecke, KM;Wyss, JM;Carroll, SL
通讯作者：
Carroll, SL