Intrinsic plasticity in CA1 pyramidal neurons: Role of calcium(2+)- and sodium(+)-activated potassium currents in aging and Alzheimer's disease.

摘要

Behavioral plasticity is critical for survival and reflects the malleability of the central nervous system in response to ever changing environmental demands. Studies from human patients with lesions of the hippocampus demonstrate its critical role in the formation of conscious (declarative) memories. Combinations of biophysical, anatomical and molecular assays have been used to identify cellular alterations that occur during or after learning tasks in animal models. Two mechanisms of information storage - changes in synaptic efficacy and intrinsic neuronal excitability - have been observed in hippocampal neurons from animals trained on associative learning tasks. Studies from our laboratory and others demonstrate that a reduction in intrinsic excitability of neurons in the hippocampus contribute to learning and memory deficits associated with aging. However, the pathological consequence of Alzheimer's disease (AD) on neuronal excitability has gone mostly unexplored. Therefore, the present thesis explores methods to expedite studies of learning-related intrinsic plasticity and applies these findings to a mouse model of AD. Specifically, we investigate the effects of varying neuronal activity-patterns and different intracellular anions on the post-burst afterhyperpolarization (AHP), an index of neuronal excitability. Additionally, we examine the effects of the rapid and emotionally-based associative learning paradigm, trace-fear conditioning, on the AHP of CA1 pyramidal neurons. The AHP is inversely related to excitability; therefore, we hypothesize that the acquisition of trace-fear will result in reduction of the AHP and concomitant increase in neuronal firing rate. Finally, we characterize the behavioral, biophysical and pathological consequences of AD using a transgenic mouse that expresses five familial AD mutations. The findings detailed in this thesis first describe a model of "learning"-related AHP plasticity in vitro, as well as outlining critical methodological considerations for the study of AHP plasticity in whole-cell neuron recordings. Second, we demonstrate a learning-related reduction in the Ca2+-dependent AHP following trace-fear conditioning. Third, this work provides insight into mechanisms underlying learning and memory impairments in a mouse model of AD. We provide a novel target for regulation of neuronal excitability in hippocampal neurons that may be useful in the design of cognitive enhancers for the elderly and patients with AD.