Temporal lobe epilepsy (TLE) is a common cause of seizures refractory to medical and surgical treatment. Increased seizure propensity in TLE is likely caused by abnormal neuronal excitability. An important controller of neuronal excitability i the hyperpolarization-activated current, Ih, which is mediated by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel. HCN channels are comprised of homo- or heteromeric assemblies of four pore-forming subunits (HCN1-4), which in hippocampal neurons associate with an auxiliary subunit, tetratricopeptide repeat (TPR)-containing Rab8b interacting protein (TRIP8b). HCN channels are markedly enriched in hippocampal pyramidal neuron dendrites, but these channels are mislocalized away from the dendritic plasma membrane in a rodent model of TLE, leading to abnormal neuronal excitability. We reason that blocking or reversing this channel mislocalization and the resultant hyperexcitability could reduce or eliminate recurrent seizures in TLE. Thus, whereas existing treatments uniformly target the symptoms of epilepsy by directly reducing neuronal excitability, our work stands to elucidate the upstream molecular changes leading to epilepsy that could establish novel therapeutic targets for preventing or reversing epileptogenesis. Ion channel localization and function is often controlled by phosphorylation of subunit proteins at specific sites. Along these lines, we have shown that normal HCN channel trafficking in hippocampal pyramidal neuron dendrites requires TRIP8b and activation of N-methyl-D-aspartate receptors (NMDAR) and calmodulin-dependent protein kinase II (CaMKII) activity. We propose to further characterize the role of HCN channel subunit phosphorylation in controlling HCN channel localization and function in normal and epileptic hippocampus. We hypothesize that 1) HCN channel localization in neurons is regulated by HCN channel subunit phosphorylation, 2) epileptogenesis leads to changes in HCN channel subunit phosphorylation that cause aberrant channel localization and function in TLE, and 3) manipulating HCN channel subunit phosphorylation can prevent HCN channel mislocalization and reduce recurrent seizures in temporal lobe epilepsy (TLE). To address these hypotheses, we propose to use physiological, cell biological and biochemical techniques to address the following specific aims: 1) to identify sites of HCN channel subunit phosphorylation in the normal and epileptic hippocampus, 2) to determine whether HCN channel subunit phosphorylation regulates channel localization, 3) to determine if blocking epilepsy-associated changes in HCN channel phosphorylation prevents channel mislocalization and recurrent seizures in TLE.
Recurring, unprovoked brain seizures are a significant cause of disability and injury in patients with epilepsy. We are studying the molecular basis for seizure recurrence in temporal lobe epilepsy (TLE), a common form of epilepsy that is often refractory to existing medical and surgical treatments, with the goal of identifying new and more effective treatments.
| Fisher, Daniel W; Han, Ye; Lyman, Kyle A et al. (2018) HCN channels in the hippocampus regulate active coping behavior. J Neurochem 146:753-766 |
| Frigerio, Federica; Flynn, Corey; Han, Ye et al. (2018) Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells. Mol Neurobiol 55:7500-7511 |
| Zobeiri, Mehrnoush; Chaudhary, Rahul; Datunashvili, Maia et al. (2018) Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels. Brain Struct Funct 223:1537-1564 |
| Fisher, Daniel W; Luu, Phillip; Agarwal, Neha et al. (2018) Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice. PLoS One 13:e0193012 |
| Yun, Sanghee; Reynolds, Ryan P; Petrof, Iraklis et al. (2018) Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive. Nat Med 24:658-666 |
| Hedrick, Tristan P; Nobis, William P; Foote, Kendall M et al. (2017) Excitatory Synaptic Input to Hilar Mossy Cells under Basal and Hyperexcitable Conditions. eNeuro 4: |
| Lyman, Kyle A; Han, Ye; Heuermann, Robert J et al. (2017) Allostery between two binding sites in the ion channel subunit TRIP8b confers binding specificity to HCN channels. J Biol Chem 292:17718-17730 |
| Chen, Hao; Judkins, Jonathon; Thomas, Cheddhi et al. (2017) Mutant IDH1 and seizures in patients with glioma. Neurology 88:1805-1813 |
| Kurz, Jonathan E; Chetkovich, Dane M (2017) Understanding Network Connections Connects Genotype to Epilepsy Phenotype. Epilepsy Curr 17:239-240 |
| Lyman, Kyle A; Han, Ye; Chetkovich, Dane M (2017) Animal models suggest the TRIP8b-HCN interaction is a therapeutic target for major depressive disorder. Expert Opin Ther Targets 21:235-237 |
Showing the most recent 10 out of 31 publications
