Angelman Syndrome (AS) is an autism spectrum disorder characterized by developmental delay, lack of speech, and epilepsy. Seizures are present in over 90% of AS patients, profoundly impacting their quality of life and that of their caregivers. AS is caused by deletion or mutation of the gene UBE3A, and AS model mice harbor a null mutation in UBE3A. Despite the high seizure susceptibility in AS, abnormalities in inhibitory neurotransmission have been largely unstudied. AS patients and model mice also exhibit abnormal EEG rhythms and seizures of neocortical origin, I propose that a well-defined inhibitory synaptic deficit in the neocortex occurs in the absence of Ube3a. Identifying such a deficit will provide insight into the treatment of epilepsy in AS individuals. I will use an AS model mouse and take advantage of the well-characterized circuitry of the visual cortex to determine the synaptic basis for the seizures in AS patients. AS model mice (UBE3A maternal null mutation) exhibit spontaneous and evoked seizures despite having a reduction in excitatory synapses. This suggests that the loss of Ube3a may cause an even more profound loss of inhibitory neurotransmission. To test this possibility, I will first employ in vitro electrophysiology to test the involvement of Ube3a in the establishment of excitatory/inhibitory balance in neocortical circuits. Second, I will use a combination of electrophysiological and viral-mediated gene expression to determine cell type-specific contributions to circuit abnormalities in the AS brain. Finally, I will determine if the loss of inhibition leads to changes in network and seizure activity in vitro and in vivo. These studies will demonstrate the cortical circuit abnormalities that may predispose AS individuals to epilepsy. In preliminary experiments, I have found target cell-specific deficits in inhibition that underlie an inhibitory/excitatory imbalance in the AS neocortex. My data suggest, for the first time, a synaptic basis for why individuals with AS are prone to epilepsy.
Angelman syndrome (AS) is an autism spectrum disorder distinguished by severe intellectual disabilities, EEG abnormalities, gait disturbances, disrupted sleep patterns, and profound language impairment. Seizures are present in over 90% of AS patients, significantly imposing on their quality of life and that of their caregivers. This proposal will investigate the mechanisms that underlie seizure susceptibility in AS model mice in order to guide the development of future epilepsy therapeutics in individuals with AS or related neurodevelopmental disorders.