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.
|Pan, Yuan; Bhattarai, Sajag; Modestou, Modestos et al. (2014) TRIP8b is required for maximal expression of HCN1 in the mouse retina. PLoS One 9:e85850|
|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|
|Brager, Darrin H; Lewis, Alan S; Chetkovich, Dane M et al. (2013) Short- and long-term plasticity in CA1 neurons from mice lacking h-channel auxiliary subunit TRIP8b. J Neurophysiol 110:2350-7|
|Kanyshkova, Tatyana; Meuth, Patrick; Bista, Pawan et al. (2012) Differential regulation of HCN channel isoform expression in thalamic neurons of epileptic and non-epileptic rat strains. Neurobiol Dis 45:450-61|
|Marcelin, Beatrice; Liu, Zhiqiang; Chen, Yuncai et al. (2012) Dorsoventral differences in intrinsic properties in developing CA1 pyramidal cells. J Neurosci 32:3736-47|
|Cao, Yan; Pahlberg, Johan; Sarria, Ignacio et al. (2012) Regulators of G protein signaling RGS7 and RGS11 determine the onset of the light response in ON bipolar neurons. Proc Natl Acad Sci U S A 109:7905-10|
|Wilkars, Wiebke; Liu, Zhiqiang; Lewis, Alan S et al. (2012) Regulation of axonal HCN1 trafficking in perforant path involves expression of specific TRIP8b isoforms. PLoS One 7:e32181|
|Bankston, John R; Camp, Stacey S; DiMaio, Frank et al. (2012) Structure and stoichiometry of an accessory subunit TRIP8b interaction with hyperpolarization-activated cyclic nucleotide-gated channels. Proc Natl Acad Sci U S A 109:7899-904|
|Khurana, Sukant; Liu, Zhiqiang; Lewis, Alan S et al. (2012) An essential role for modulation of hyperpolarization-activated current in the development of binaural temporal precision. J Neurosci 32:2814-23|
|Lewis, Alan S; Vaidya, Sachin P; Blaiss, Cory A et al. (2011) Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. J Neurosci 31:7424-40|
Showing the most recent 10 out of 15 publications