The goal of the proposed experiments is to understand the functional role of calcium/calmodulin-dependent protein kinase II (CaMKII) in regulating learning-associated changes in excitability of hippocampal neurons. It is well established that CaMKII is a key molecule required for learning and memory. Previous genetic and pharmacological studies have provided evidence for CaMKII-dependent modifications of synaptic strength during learning, although little is known about its role in the modulation of neuronal excitability, another important cellular mechanism of learning and memory. Neuronal excitability is primarily determined by the properties of ion channels: K+-channels, in particular, are key components in tuning of the membrane excitability of neurons. The working hypothesis to be tested is that CaMKII not only controls hippocampal synaptic plasticity but also modulates K+-channel properties accounting for an increase in hippocampal neuronal excitability during learning and memory consolidation. Analysis of alphaCaMKII mutant mice will determine the role of CaMKII as a molecular constituent responsible for learning-related excitability changes. The mutant mouse we will use is one that carries a point mutation at an autophosphorylation site in the alphaCaMKII gene (T286A) and consequently loses the function of this kinase. This study will clarify the role of alphaCaMKII in the increase in excitability of CA1 pyramidal neurons as evidenced by reduced afterhyperpolarization (AHP) during the acquisition of hippocampus-dependent associative learning (trace eyeblink conditioning) and spatial learning (water maze) tasks. Whole cell voltage-clamp recording will determine which components of outward potassium currents (SlAHP,IAHP, IM, IC, IA or IH) play a critical role in alphaCaMKII -mediated regulation of CA1 neuron excitability during hippocampal learning. Our integrated analyses of alphaCaMKII T2sBA mutants with behavioral, biophysical, biochemical and pharmacogenetic approaches will evaluate a molecular mechanism by which alphaCaMKII -mediated phosphorylation of K-channel subunits following muscarinic neurotransmission could contribute to hippocampal learning processes by regulating neuronal excitability. Further understanding of how CaMKII functions to establish learning and memory in brain will have relevance to the better understanding of mechanisms underlying learning deficits or dementia, and to developing novel strategies to treat learning disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
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Asanuma, Chiiko
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Northwestern University at Chicago
Schools of Medicine
United States
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Ohno, Masuo (2016) Alzheimer's therapy targeting the ?-secretase enzyme BACE1: Benefits and potential limitations from the perspective of animal model studies. Brain Res Bull 126:183-198
Devi, Latha; Ohno, Masuo (2012) Mitochondrial dysfunction and accumulation of the ýý-secretase-cleaved C-terminal fragment of APP in Alzheimer's disease transgenic mice. Neurobiol Dis 45:417-24
Kimura, Ryoichi; Devi, Latha; Ohno, Masuo (2010) Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer's disease transgenic mice. J Neurochem 113:248-61
Devi, Latha; Ohno, Masuo (2010) Genetic reductions of beta-site amyloid precursor protein-cleaving enzyme 1 and amyloid-beta ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer's disease model mice. Eur J Neurosci 31:110-8
Devi, Latha; Ohno, Masuo (2010) Phospho-eIF2? level is important for determining abilities of BACE1 reduction to rescue cholinergic neurodegeneration and memory defects in 5XFAD mice. PLoS One 5:e12974
Devi, Latha; Alldred, Melissa J; Ginsberg, Stephen D et al. (2010) Sex- and brain region-specific acceleration of ?-amyloidogenesis following behavioral stress in a mouse model of Alzheimer's disease. Mol Brain 3:34
Sametsky, Evgeny A; Disterhoft, John F; Ohno, Masuo (2009) Autophosphorylation of alphaCaMKII downregulates excitability of CA1 pyramidal neurons following synaptic stimulation. Neurobiol Learn Mem 92:120-3
Kimura, Ryoichi; Ohno, Masuo (2009) Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis 33:229-35
Ohno, Masuo (2009) Failures to reconsolidate memory in a mouse model of Alzheimer's disease. Neurobiol Learn Mem 92:455-9
Kimura, Ryoichi; Silva, Alcino J; Ohno, Masuo (2008) Autophosphorylation of alphaCaMKII is differentially involved in new learning and unlearning mechanisms of memory extinction. Learn Mem 15:837-43

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