title: Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome.
abstract: 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.
authors.affiliation: Department of Biological Science, University of Southern California, Los Angeles, CA, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Baudry
authors.forename: Eniko
authors.initials: E
authors.lastname: Kramar
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Xu
authors.forename: Homera
authors.initials: H
authors.lastname: Zadran
authors.forename: Stephanie
authors.initials: S
authors.lastname: Moreno
authors.forename: Gary
authors.initials: G
authors.lastname: Lynch
authors.forename: Christine
authors.initials: C
authors.lastname: Gall
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Bi
mesh_terms: D000199:Actins / Q000378:metabolism*; D017204:Angelman Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007858:Learning / Q000187:drug effects* / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D058105:Polymerization / Q000187:drug effects; D018091:Receptors, AMPA / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
chemical_list: D000199:Actins; D018091:Receptors, AMPA; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases