کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
3069715 | 1580680 | 2012 | 6 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome](/preview/png/3069715.png)
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: ‘AS mice’) 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.
► LTP consolidation is impaired in a mouse model of Angelman syndrome (AS).
► Actin polymerization following theta burst stimulation is impaired in AS mice.
► CX929 treatment promotes LTP consolidation and actin polymerization.
► CX929 treatment enhances behavioral performance in a fear-conditioning paradigm.
Journal: Neurobiology of Disease - Volume 47, Issue 2, August 2012, Pages 210–215