Small conductance calcium-activated potassium channels (SK1-3) are widely distributed throughout the brain and other organs. In hippocampal CA1 pyramidal neurons, SK2 channel- mediated hyperpolarization limits NMDAR activation, thereby resulting in a fine tuning of activity- dependent Ca2+ influx. By controlling NMDAR opening, SK2 channels also influence neurotransmission, neuronal firing frequency, synaptic plasticity, and learning and memory. While there is a wealth of information on SK2 channel gating and kinetics, and Ca2+ sensitivity, little is known about the regulation of SK2 channel numbers in synapses. The proposed studies intend to fill this knowledge gap by testing the hypothesis that the E3 ligase, UBE3A, whose maternal deletion results in Angelman syndrome, contributes to the removal of SK2 channels from the postsynaptic membrane and subsequent degradation, a process that is critical for both synaptic plasticity and memory formation. The hypothesis posits that synaptic SK2 channel number is elevated in Ube3a-deficient mice, as compared to wild-type littermates and that blocking SK2 channels could ameliorate some of the cognitive deficits present in these mice. The proposed studies will use a variety of integrated approaches, including electrophysiology, primary neuronal cultures, genetic construct reconstitution, biochemical assays and innovative fluorescent assays. Since SK2 channels are widely expressed in mammalian brain, the outcome of the proposal will have significant implications for a vast array of neurologic/neuropsychiatric disorders.
While maternal UBE3A deletion results in Angelman syndrome its overexpression has been linked to autism. Likewise, overactivation or inhibition of SK2 channels is associated with either cognitive impairment or epilepsy, respectively. However, whether there is a direct link between these two proteins is unknown. The proposed studies address the regulation of SK2 channels by UBE3A and will provide critical information that can be used for identifying new therapeutic targets for a wide range of neurologic/neuropsychiatric disorders.
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