All ETDs from UAB

Advisory Committee Chair

John J Hablitz

Advisory Committee Members

Linda Wadiche

Rita Cowell

Scott Wilson

Michael Wyss

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

GABAergic interneurons provide the main source of inhibition in the neocortex and are important in regulating neocortical network activity. In the presence of the K+ channel blocker 4-AP and the glutamate receptor blockers, CNQX and D-APV, large amplitude evoked and spontaneous depolarizing responses are observed in the neocortex. These large propagating responses are blocked by GABAA receptor antagonists indicating that these events are due to synchronized activity of GABAergic interneurons. Cortical GABAergic networks are comprised of several types of interneurons, each with its own protein expression pattern, receptor profile, firing properties, synaptic targets and role in network activity. Voltage-gated ion channels, especially A-type K+ channels, differentially regulate passive membrane properties, action potential (AP) waveform, and repetitive firing properties in neurons depending on channel composition and localization. Additionally, hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and the corresponding Ih current are known modulators of pyramidal cell intrinsic excitability and excitatory network activity. How HCN channels functionally modulate excitability of individual GABAergic interneurons and inhibitory networks as a whole remains unknown. I examined the effect of 4-AP on intrinsic excitability of two classes of interneurons fast-spiking basket cells (FS-BCs) and Martinotti cells (MCs). 4-AP increased the duration of APs in both FS-BCs and MCs. The repetitive firing properties of MCs were differentially affected compared to FS-BCs. I additionally examined the effect of Ih inhibition on synchronous GABAergic depolarizations and synaptic integration of depolarizing inhibitory postsynaptic potentials (IPSPs). Application of the HCN channel antagonist ZD 7288 inhibited the robust Ih-mediated sag responses in MCs, as well as the minimal sag response in FS-BCs. ZD 7288 enhanced the amplitude and area of evoked GABAergic depolarizations in both cell types. Similarly, the frequency and area of spontaneously occurring GABAergic depolarizations in FS-BCs and MCs were increased in presence of ZD 7288. However, synaptic integration of IPSPs in MCs was significantly enhanced, whereas summation of IPSPs in FS-BCs remained unaltered. These results indicate that 4-AP differentially alters the firing properties of interneurons, suggesting MCs and FS-BCs uniquely participate in GABAergic network synchronization. Furthermore, enhancement of GABAergic network synchronization by Ih inhibition indicates HCN channels attenuate inhibitory network activity.

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