This proposal is designed to investigate the relationship between the hyperpolarization-activated cation current (I{h}) and intrinsic excitability (IE) of CA1 pyramidal neurons. Previous work demonstrated enhanced or reduced IE following the induction of long-term depression (LTD) and long-term potentiation (LTP), respectively, and several physiological studies have implicated I{h} as the most likely mediator of IE plasticity (Fan et al., 2005;Brager and Johnston, 2007;Narayanan and Johnston, 2007). However, all evidence describing the plasticity of I{h}mediated IE comes from indirect measurements of I{h} using the whole cell current-clamp method. The mechanism underlying this phenomenon therefore remains unclear, and represents a substantial gap in our understanding of the regulation of IE in these neurons. This proposal investigates the biophysical mechanism of IE plasticity directly, using voltage-clamp methods capable of determining the biophysical properties of single h-channels (the ion channels responsible for I{h}) as the primary tool. Specifically, the reduction in IE following LTP and the increase in IE following LTD will be investigated. This work will represent a substantial contribution to our understanding of IE homeostasis in CA1 pyramidal neurons.

Public Health Relevance

Several recent reports have demonstrated a link between temporal lobe epilepsy (TLE) and I{h} in CA1 pyramidal neurons (Shin et al., 2008;Jung et al., 2007). I{h} functions as an activity-dependent regulator of intrinsic excitability (IE) in these neurons, and the observed pathophysiology associated with TLE likely stems from a failure of I{h}-mediated IE homeostasis. This proposal is designed to directly investigate the currently unknown biophysical mechanism for I{h}-mediated IE homeostasis, and will help to shed light on the pathophysiology of the acquired I{h}-channelopathy associated with TLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32MH090665-03
Application #
8289592
Study Section
Special Emphasis Panel (ZRG1-F03B-H (20))
Program Officer
Desmond, Nancy L
Project Start
2010-06-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$52,190
Indirect Cost
Name
University of Texas Austin
Department
None
Type
Organized Research Units
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712