This proposal is designed to investigate the relationship between the hyperpolarization-activated cation current (Ih) 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 Ih 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 Ihmediated IE comes from indirect measurements of Ih 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 Ih) 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 Ih in CA1 pyramidal neurons (Shin et al., 2008;Jung et al., 2007). Ih 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 Ih-mediated IE homeostasis. This proposal is designed to directly investigate the currently unknown biophysical mechanism for Ih-mediated IE homeostasis, and will help to shed light on the pathophysiology of the acquired Ih-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 |
