Effects of the synthetic neurosteroid ganaxolone on seizure activity and behavioral deficits in an Angelman syndrome mouse model

• Published in: Neuropharmacology 2017-04, Vol.116, p.142-150
• Main Authors: Ciarlone, Stephanie L., Wang, Xinming, Rogawski, Michael A., Weeber, Edwin J.
• Format: Article
• Language: English
• Subjects: Angelman syndrome; Angelman Syndrome - drug therapy; Angelman Syndrome - physiopathology; Angelman Syndrome - psychology; Animals; Anti-Anxiety Agents - pharmacology; Anticonvulsants - pharmacology; Anxiety; Anxiety - drug therapy; Anxiety - physiopathology; Disease Models, Animal; Female; GABA; Ganaxolone; Hippocampus - drug effects; Hippocampus - physiopathology; Long-Term Potentiation - drug effects; Long-Term Potentiation - physiology; Male; Maze Learning - drug effects; Maze Learning - physiology; Memory, Short-Term - drug effects; Memory, Short-Term - physiology; Mice, Knockout; Motor Activity - drug effects; Motor Activity - physiology; Neurosteroid; Pentylenetetrazole; Pregnanolone - analogs & derivatives; Pregnanolone - pharmacology; Receptors, GABA-A - metabolism; Seizure; Seizures - drug therapy; Seizures - physiopathology; Seizures - psychology; Spatial Memory - drug effects; Spatial Memory - physiology; Tissue Culture Techniques; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.12.009

Angelman syndrome (AS) is a rare neurogenetic disorder characterized by severe developmental delay, motor impairments, and epilepsy. GABAergic dysfunction is believed to contribute to many of the phenotypic deficits seen in AS. We hypothesized that restoration of inhibitory tone mediated by extrasynaptic GABAA receptors could provide therapeutic benefit. Here, we report that ganaxolone, a synthetic neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, was anxiolytic, anticonvulsant, and improved motor deficits in the Ube3a-deficient mouse model of AS when administered by implanted mini-pump for 3 days or 4 weeks. Treatment for 4 weeks also led to recovery of spatial working memory and hippocampal synaptic plasticity deficits. This study demonstrates that ganaxolone ameliorates many of the behavioral abnormalities in the adult AS mouse, and tolerance did not occur to the therapeutic effects of the drug. The results support clinical studies to investigate ganaxolone as a symptomatic treatment for AS. •Ganaxolone was anxiolytic, anticonvulsant, and improved motor deficits in AS mice.•Four weeks of ganaxolone treatment recovered spatial working memory and hippocampal LTP deficits.•Tolerance did not develop to the therapeutic effects of ganaxolone.•Modulation of extrasynaptic GABAA receptors may provide symptomatic benefits in AS.