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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15MH101703-01A1
Application #
8762978
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Asanuma, Chiiko
Project Start
2014-08-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2017-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Western University of Health Sciences
Department
Other Basic Sciences
Type
Schools of Osteopathic Medicine
DUNS #
City
Pomona
State
CA
Country
United States
Zip Code
91766
Bi, Xiaoning; Sun, Jiandong; Ji, Angela X et al. (2016) Potential therapeutic approaches for Angelman syndrome. Expert Opin Ther Targets 20:601-13
Baudry, Michel; Bi, Xiaoning (2016) Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration. Trends Neurosci 39:235-45
Sun, Jiandong; Liu, Yan; Tran, Jennifer et al. (2016) mTORC1-S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice. Cell Mol Life Sci 73:4303-4314
Liu, Yan; Wang, Yubin; Zhu, Guoqi et al. (2016) A calpain-2 selective inhibitor enhances learning & memory by prolonging ERK activation. Neuropharmacology 105:471-7
Liu, Yan; Sun, Jiandong; Wang, Yubin et al. (2016) Deleting both PHLPP1 and CANP1 rescues impairments in long-term potentiation and learning in both single knockout mice. Learn Mem 23:399-404
Sun, Jiandong; Liu, Yan; Moreno, Stephanie et al. (2015) Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function. J Neurosci 35:4706-18
Sun, Jiandong; Zhu, Guoqi; Liu, Yan et al. (2015) UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis. Cell Rep 12:449-61
Bi, Xiaoning; Sun, Jiandong; Baudry, Michel (2015) Yin-and-Yang of mTORC1/C2 in Angelman syndrome mice. Oncotarget 6:13844-5
Baudry, Michel; Zhu, Guoqi; Liu, Yan et al. (2015) Multiple cellular cascades participate in long-term potentiation and in hippocampus-dependent learning. Brain Res 1621:73-81
Zhu, Guoqi; Liu, Yan; Wang, Yubin et al. (2015) Different patterns of electrical activity lead to long-term potentiation by activating different intracellular pathways. J Neurosci 35:621-33

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