Synaptic Ca2+-activated K+ channels, SK2 channels, influence neurotransmission, synaptic plasticity, and learning and memory. Blocking SK channel activity facilitates synaptic plasticity and learning and memory while overexpressing SK2 or pharmacologically increasing SK channel activity impairs these processes. We discovered the molecular and cellular mechanisms that are likely responsible for the effects of SK2 channels on synaptic plasticity, the leading model for cellular changes underlying learning and memory. We showed that the activity of SK2 channels in the dendritic spines of hippocampal CA1 pyramidal neurons is coupled to NMDAR activity. Synaptically evoked Ca2+ entry into spines activates synaptic SK2 channels that repolarize the spine membrane potential, thereby favoring Mg2+ re-block of NMDARs, and thus limiting Ca2+ influx through NMDARs that is crucial to the induction of synaptic plasticity. In addition we showed that plasticity-dependent trafficking of SK2 channels itself contributes to the expression of NMDAR-dependent long-term potentiation. New results suggest that SK2 channel trafficking is linked to NMDAR trafficking that is orchestrated and coordinated by a novel family of synaptic scaffolding proteins to affect synaptic dynamics. We will use an integrated repertoire of electrophysiology in fresh brain slice preparations and recordings from transfected cells, biochemical pull-down assays and reconstitutions experiments, and innovative immuno-electron microscopy to examine the molecular and cellular mechanisms that engender the orchestrated trafficking of SK2 channels and NMDARs. The results have profound implications for novel interventional strategies to treat a wide range of cognitive disorders.

Public Health Relevance

Long-term synaptic plasticity is widely thought to be the cellular substrate for learning and memory. The proposed research will illuminate novel pathways and molecules employed by neurons in the brain to orchestrate cellular rearrangements that engender synaptic plasticity. Therefore, this work will reveal potential therapeutic targets for a wide range of cognitive and other brain disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH093599-01A1
Application #
8289226
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Asanuma, Chiiko
Project Start
2012-06-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$309,971
Indirect Cost
$108,691
Name
Oregon Health and Science University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Kim, Gukhan; Luján, Rafael; Schwenk, Jochen et al. (2016) Membrane palmitoylated protein 2 is a synaptic scaffold protein required for synaptic SK2-containing channel function. Elife 5:
Wang, Kang; Mateos-Aparicio, Pedro; Hönigsperger, Christoph et al. (2016) IK1 channels do not contribute to the slow afterhyperpolarization in pyramidal neurons. Elife 5:e11206
Wang, Kang; Kelley, Melissa H; Wu, Wendy W et al. (2015) Apamin Boosting of Synaptic Potentials in CaV2.3 R-Type Ca2+ Channel Null Mice. PLoS One 10:e0139332
Wang, Kang; Lin, Mike T; Adelman, John P et al. (2014) Distinct Ca2+ sources in dendritic spines of hippocampal CA1 neurons couple to SK and Kv4 channels. Neuron 81:379-87
Ballesteros-Merino, Carmen; Lin, Mike; Wu, Wendy W et al. (2012) Developmental profile of SK2 channel expression and function in CA1 neurons. Hippocampus 22:1467-80
Ohtsuki, Gen; Piochon, Claire; Adelman, John P et al. (2012) SK2 channel modulation contributes to compartment-specific dendritic plasticity in cerebellar Purkinje cells. Neuron 75:108-20
Lin, Mike T; Adelman, John P; Maylie, James (2012) Modulation of endothelial SK3 channel activity by Caýý+dependent caveolar trafficking. Am J Physiol Cell Physiol 303:C318-27
Deignan, J; Lujan, R; Bond, C et al. (2012) SK2 and SK3 expression differentially affect firing frequency and precision in dopamine neurons. Neuroscience 217:67-76
Wimmer, Ralf D; Astori, Simone; Bond, Chris T et al. (2012) Sustaining sleep spindles through enhanced SK2-channel activity consolidates sleep and elevates arousal threshold. J Neurosci 32:13917-28
Adelman, John P; Maylie, James; Sah, Pankaj (2012) Small-conductance Ca2+-activated K+ channels: form and function. Annu Rev Physiol 74:245-69

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