CaMKII and Neuronal Excitability Changes in Learning

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): 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, biophy
StatusFinished
Effective start/end date12/1/0211/30/07

Funding

  • National Institute of Mental Health (5 R01 MH067251-04 (Revised))

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