Date of Award

2014

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Lawrence M. Grover

Second Advisor

Todd Green

Third Advisor

Richard Egleton

Fourth Advisor

Elsa Mangiarua

Fifth Advisor

Sasha Zill

Abstract

Schaffer collaterals are the unmyelinated axons of pyramidal neurons in the CA3 area of the hippocampus, a brain structure essential for memory formation. Schaffer collateral axons conduct electrical signals in the form of action potentials from CA3 pyramidal cells to synaptic terminals in area CA1. The fidelity with which these axons conduct action potentials determines the nature of the information which can be transmitted between areas CA3 and CA1. Conduction fidelity may be affected by both normal and abnormal patterns of firing, fluctuations in ion concentration, and some drugs and toxins. In this dissertation, I examined the function of Schaffer collateral axons in rat (male and female) hippocampal slices during high-frequency and burst stimulation. I recorded single axon responses from individual neurons using whole-cell patch-clamp recording, and compound action potentials (fiber volleys or population spikes) using extracellular recordings. In these recordings, I observed that Schaffer collaterals undergo frequency-dependent changes in function, with differences between proximal and distal axon regions. Early during stimulation, fiber volleys recorded from the distal portions of these axons increased in amplitude and decreased in conduction latency, indicating a state of enhanced excitability (hyper-excitability), and later during stimulation decreased in amplitude and increased in latency, indicating a state of depressed excitability. In contrast, the proximal portions of these axons showed only amplitude depression and latency increase. To determine the cause(s) of the functional changes and regional differences, I examined the effects of altering extracellular divalent cations, and blocking voltage-gated calcium (CaV) channels, calcium-dependent potassium (KCa) channels, and voltage-dependent potassium (KV) channels. I found that the biphasic changes in distal axon function were dependent on extracellular calcium, but not dependent upon CaV or KCa channels. Non-specific blockade of KV channels enhanced amplitude depression and latency increases, but these effects were not replicated by selective KV channel blockade. In summary, the early hyper-excitable state of distal Schaffer collaterals is regulated by extracellular Ca2+, but the effects of extracellular Ca2+ are not mediated by CaV channels. Also, KV channels are important in maintaining excitability, since non-specific blockade shortens the hyper-excitable period and leads to more rapid and greater depression of excitability. Because specific KV channel blockers could not reproduce the effects of non-specific KV channel block, I suggest that multiple KV channel types regulate excitability in a redundant manner. In conclusion, the distal Schaffer collaterals are functionally adapted to maintain conduction fidelity by enhancement of excitability during brief periods of activity. This ability to maintain conduction fidelity during brief periods of activity may be critical for successful action potential propagation throughout the long and extensively branched Schaffer collateral axonal arbor during the physiological burst firing of CA3 pyramidal neurons.

Subject(s)

Cognitive neuroscience.

Nervous system.

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