The role of the mammalian hippocampus in different aspects of learning and memory, and its relationship to several neurological disorders, is well established. A prominent hypothesis that has gained traction over the past two decades is that intrinsic plasticity of voltage-gated ion channels (VGICs) along with the well- established plasticity in synaptic strength could be the cellular mechanisms underlying these crucial hippocampal functions. This project will focus on plasticity of VGICs in response to graded release or depletion of calcium from the endoplasmic reticulum (ER) in hippocampal pyramidal neurons. The overall theme of this work is that release of calcium from the ER triggers plasticity of intrinsic neuronal properties, which, in turn, acts either as a cellular correlate of an engram r as a homeostatic mechanism to counteract altered neuronal excitability. A recent research article by the co-PIs demonstrating the existence of plasticity in the hyperpolarization-activated nonspecific-cationic h current in response to the depletion of ER stores provides the background for this exploratory grant proposal. Here, we intend to pursue this form of intrinsic plasticity in greater detail, with specific reference to graded release of calcium from the ER, rather than through depletion of ER stores. Furthermore, motivated by the existence of activity-dependent plasticity mechanisms in multiple VGICs, we also propose to explore other dendritic VGICs that may change in response to depletion as well as graded release of calcium from the ER stores. Specifically, we propose to look at the A-type potassium current, which regulates dendritic excitability and has been demonstrated to undergo various forms of activity- dependent plasticity. We also aim to arrive at a better understanding of the mechanisms underlying these different forms of intrinsic plasticity induced by graded release or depletion of calcium from the ER. We postulate that intrinsic plasticity induced by graded release of calcium from the ER would play a role in encoding memory, whereas depletion-induced intrinsic plasticity would act a neuroprotective mechanism that reduces excitability after depletion of calcium stores, which is triggered through altered network activity during pathological conditions.
Depletion of ER stores has been linked to several neurological disorders including epilepsy, and dendritic plasticity in h- and A-type potassium channels have been observed under epileptic conditions. Our experiments will provide putative signaling pathways linking store depletion to epilepsy-induced channelopathies in dendritic h and A-type K+ channels.
|Clemens, Ann M; Johnston, Daniel (2014) Age- and location-dependent differences in store depletion-induced h-channel plasticity in hippocampal pyramidal neurons. J Neurophysiol 111:1369-82|
|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|