Abstracts

Rationale: Angelman syndrome (AS) is a neurogenetic disorder associated with profound intellectual disability, speech impairment, movement and balance disorder, a unique behavioral profile, sleep disturbances, and refractory epilepsy. AS results from a neuronal deficiency of functional UBE3A (also known as E6-AP), an E3 ubiquitin ligase encoded by the UBE3A gene. UBE3A is imprinted in neurons, such that expression is nearly exclusively from the maternal chromosome. The seizure types, sleep disturbances, and EEG changes seen in AS individuals suggest that dysfunction of thalamocortical circuitry plays a prominent role in the phenotype. In maternal Ube3a knockout (AS) mice, we have recently shown that Ube3a expression is imprinted in reticular nucleus and ventrobasal nucleus neurons of the thalamus. To begin to understand the role of Ube3a in regulating thalamocortical circuitry function, we evaluated GABA-A receptor (GABAR) expression and function in AS and WT mice. GABARs are pentameric receptors composed primarily of a combination of ?, ? and either a ? or ? subunits selected from six ?, three ?, one ?, and three ? subunit subtypes. The distribution of specific subtypes is highly brain region and cell type specific, and varies during development and in certain disease states. The presence of a specific subunit subtype confers different pharmacological and physiological properties to receptor isoforms. Methods: In this study, we used a combination of whole cell patch-clamp recordings of acutely prepared thalamic slices and immunoblotting of thalamic homogenates from (P8-28) AS and WT mice to investigate potential alterations in GABAergic signaling. Results: Over the age range studied, we discovered alterations in the normal developmental profile of spontaneous GABAR-mediated transmission. Further, we measured a trend towards increased tonic current in AS mice compared to wild types, particularly in animals older than P17. This tonic current showed a greater response to the ? subunit subtype-preferring agonist DS2. Consistent with this finding, we detected an upregulation of ?4 and ? receptor subunit subtypes in the thalamus of P17-28 AS mice relative to WT littermates (but not at earlier ages). Conclusions: Our findings suggest that alterations in thalamic GABAR subunit expression, including upregulation of extrasynaptic receptors over the course of early development, contribute to thalamocortical dysfunction in AS. These findings may help to inform the development of new treatments to control seizures and improve the developmental outcome in this devastating disorder.