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.
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.
| Malik, Ruchi; Dougherty, Kelly Ann; Parikh, Komal et al. (2016) Mapping the electrophysiological and morphological properties of CA1 pyramidal neurons along the longitudinal hippocampal axis. Hippocampus 26:341-61 |
| Dougherty, Kelly A; Nicholson, Daniel A; Diaz, Laurea et al. (2013) Differential expression of HCN subunits alters voltage-dependent gating of h-channels in CA1 pyramidal neurons from dorsal and ventral hippocampus. J Neurophysiol 109:1940-53 |
| Dougherty, Kelly A; Islam, Tasnim; Johnston, Daniel (2012) Intrinsic excitability of CA1 pyramidal neurones from the rat dorsal and ventral hippocampus. J Physiol 590:5707-22 |
| Narayanan, Rishikesh; Dougherty, Kevin J; Johnston, Daniel (2010) Calcium store depletion induces persistent perisomatic increases in the functional density of h channels in hippocampal pyramidal neurons. Neuron 68:921-35 |
