Activity-dependent synaptic modifications (LTP/LTD) are a major candidate for the mechanism of memory. LTP involves induction, maintenance, and expression processes. This proposal seeks to elucidate the molecular basis of the maintenance process, the process that underlies the engram. The critical test of any hypothesis regarding maintenance is the ?erasure test? in which an inhibitor is applied after LTP/memory is established. If this blocks LTP/memory and the effect persists after the inhibitor is removed, the inhibitor must have erased a maintenance process. We have conducted the erasure test using an inhibitor of CaMKII (CN-peptide). We found that application of this peptide after LTP induction produced erasure of saturated LTP. We now propose two experiments that test the role of CaMKII? in memory maintenance at the behavioral level. In the first, we ask whether a dominant-negative form of CaMKII? can erase conditioned place avoidance. We present strong preliminary evidence that it does. The second test is the ?occlusion test.? It has been shown that activated kinase (CaMKII?*) enhances synaptic transmission that occludes synaptically induced LTP. We will virally express CaMKII?* and test two predictions: that because this maximally increases all synaptic weights it should destroy memory function, and furthermore, that learning under these conditions should not be possible. Preliminary evidence supporting these predictions is presented. Other experiments in this proposal are aimed at understanding the nature of the CaMKII? complex that stores the engram. There are strong reasons to suspect that what maintains LTP is actually the complex of CaMKII? with NMDAR (and perhaps also densin- 180). Studies of the binding of proteins to CaMKII have relied on in vitro work, and there has been no previous method for studying the complexes formed during actual LTP induction. Thus, crucial information regarding the complex formation and persistence is lacking. We have developed and validated a novel optical method based on FLIM-FRET. Our preliminary evidence demonstrates that LTP induction produces complex of CaMKII? with GluN2B in spines and that the formation is synapse specific. We will determine the duration of the complex under conditions that either induce short-lasting LTP (early LTP) or produce both early and late LTP. We will also examine how the duration of the complex depends on factors that enhance (e.g., BDNF) or prevent (e.g., protein synthesis inhibitors) late LTP. This approach will be extended to study the interaction of CaMKII? with densin-180. Having identified properties of the complex that underlies LTP, in vivo experiments will be conducted to test whether disruption of protein interactions within the complex can disrupt maintenance of the engram.

Public Health Relevance

Healthcare Relevance There is strong evidence that the decreased synaptic plasticity in aging and Alzheimer's involves reductions in CaMKII activation. Significant evidence now has been accumulated, suggesting that the kinase may also contribute to development of numerous pathological processes leading to neurological dysfunction and diseases such as epilepsy, neuropathic pain, and cell death during stroke [1]. Other work points to the critical role of CaMKII? in the maintenance of addiction [3].

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurobiology of Learning and Memory Study Section (LAM)
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Babcock, Debra J
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Brandeis University
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Lisman, John; Cooper, Katherine; Sehgal, Megha et al. (2018) Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability. Nat Neurosci 21:309-314
Rossetti, Tom; Banerjee, Somdeb; Kim, Chris et al. (2017) Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage. Neuron 96:207-216.e2
Lisman, John (2017) Glutamatergic synapses are structurally and biochemically complex because of multiple plasticity processes: long-term potentiation, long-term depression, short-term potentiation and scaling. Philos Trans R Soc Lond B Biol Sci 372:
Lisman, John (2017) Criteria for identifying the molecular basis of the engram (CaMKII, PKMzeta). Mol Brain 10:55
Liu, Kang K L; Hagan, Michael F; Lisman, John E (2017) Gradation (approx. 10 size states) of synaptic strength by quantal addition of structural modules. Philos Trans R Soc Lond B Biol Sci 372:
Khlestova, Elizaveta; Johnson, Jon W; Krystal, John H et al. (2016) The Role of GluN2C-Containing NMDA Receptors in Ketamine's Psychotogenic Action and in Schizophrenia Models. J Neurosci 36:11151-11157
Brandalise, Federico; Carta, Stefano; Helmchen, Fritjof et al. (2016) Dendritic NMDA spikes are necessary for timing-dependent associative LTP in CA3 pyramidal cells. Nat Commun 7:13480
Otmakhov, Nikolai; Regmi, Shaurav; Lisman, John E (2015) Fast Decay of CaMKII FRET Sensor Signal in Spines after LTP Induction Is Not Due to Its Dephosphorylation. PLoS One 10:e0130457
Sanders, Honi; Rennó-Costa, César; Idiart, Marco et al. (2015) Grid Cells and Place Cells: An Integrated View of their Navigational and Memory Function. Trends Neurosci 38:763-775
Lisman, John (2015) The challenge of understanding the brain: where we stand in 2015. Neuron 86:864-882

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