Summary Gated solely by activity-induced changes in intracellular calcium, small conductance potassium channels (SKs) are critical for a variety of functions in the CNS, from learning and memory to rhythmic activity and sleep. While there is a wealth of information on SK2 gating, kinetics and Ca2+ sensitivity, little is known regarding the regulation of SK2 subcellular localization. We report here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and over-expression in increased risk of autistic spectrum disorder. UBE3A directly ubiquitinates SK2 in the C-terminal domain, which facilitates endocytosis. In UBE3A-deficient mice, increased postsynaptic SK2 levels result in decreased NMDA receptor activation, thereby impairing hippocampal long-term synaptic plasticity. Impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2. These results elucidate a mechanism by which UBE3A directly influences cognitive function.

Spinal cord injury (SCI) is a life-shattering neurological condition that affects between 250,000 and 500,000 individuals each year with an estimated two to three million people worldwide living with an SCI-related disability. The incidence in the USA and Canada is more than that in other countries with motor vehicle accidents being the most common cause, while violence being most common in the developing nations. Its incidence is two- to fivefold higher in males, with a peak in younger adults. Apart from the economic burden associated with medical care costs, SCI predominantly affects a younger adult population. Therefore, the psychological impact of adaptation of an average healthy individual as a paraplegic or quadriplegic with bladder, bowel, or sexual dysfunction in their early life can be devastating. People with SCI are two to five times more likely to die prematurely, with worse survival rates in low- and middle-income countries. This devastating disorder has a complex and multifaceted mechanism. Recently, a lot of research has been published on the restoration of locomotor activity and the therapeutic strategies. Therefore, it is imperative for the treating physicians to understand the complex underlying pathophysiological mechanisms of SCI.

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