Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome

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• 作者：Michel Baudry^a ; ¹ ; Eniko Kramar^b ; ¹ ; Xiaobo Xu^a ; Homera Zadran^a ; Stephanie Moreno^d ; Gary Lynch^b ; ^c ; Christine Gall^c ; Xiaoning Bi^d ; ^{xbi@westernu.edu}
• 关键词：Actin ; AMPA receptor ; Hippocampus ; Learning and memory ; LTP ; UBE3A
• 刊名：Neurobiology of Disease
• 出版年：2012
• 期刊代码：80_09699961
• 类别：neu
• 出版时间：August, 2012
• 卷：47
• 期：2
• 页码：210-215
• 文件大小：607 K

摘要

Angelman syndrome (AS) is a neurodevelopmental disorder largely due to abnormal maternal expression of the UBE3A gene leading to the deletion of E6-associated protein. AS subjects have severe cognitive impairments for which there are no therapeutic interventions. Mouse models (knockouts of the maternal Ube3a gene: 鈥楢S mice鈥? of the disorder have substantial deficits in long-term potentiation (LTP) and learning. Here we report a clinically plausible pharmacological treatment that ameliorates both deficits. AS mice were injected ip twice daily for 5 days with vehicle or the ampakine CX929; drugs of this type enhance fast EPSCs by positively modulating AMPA receptors. Theta burst stimulation (TBS) produced a normal enhancement of field EPSPs in hippocampal slices prepared from vehicle-treated AS mice but LTP decreased steadily to baseline; however, LTP in slices from ampakine-treated AS mice stabilized at levels found in wild-type controls. TBS-induced actin polymerization within dendritic spines, an essential event for stabilizing LTP, was severely impaired in slices from vehicle-treated AS mice but not in those from ampakine-treated AS mice. Long-term memory scores in a fear conditioning paradigm were reduced by 50%in vehicle-treated AS mice but were comparable to values for littermate controls in the ampakine-treated AS mice. We propose that AS is associated with a profound defect in activity-driven spine cytoskeletal reorganization, resulting in a loss of the synaptic plasticity required for the encoding of long-term memory. Notably, the spine abnormality along with the LTP and learning impairments can be reduced by a minimally invasive drug treatment.