Research Abstract:
Our research focuses on mechanisms of epileptogenesis and seizure-induced brain injury in animal models of epilepsy. Both pharmacological and genetic models of epilepsy are studied on the behavioral, circuit, cellular, and molecular level. A wide variety of experimental approaches are utilized, including electrophysiological (from patch-clamping in culture cells and slice preparations to in vivo video-EEG monitoring), histological (conventional and fluorescent assays), and modern cellular imaging techniques (confocal and two-photon microscopy of in vivo, live slice, and fixed tissue preparations).
To investigate mechanisms of epileptogenesis, in pharmacological seizure models we study developmental differences in neurotransmitter systems that contribute to decreased seizure threshold in immature animals. In several genetic models of epilepsy, we are investigating the molecular mechanisms involved in epileptogenesis due to specific genetic mutations. Recently, we have focused on the novel role of astrocytic dysfunction in epileptogenesis. We have characterized seizures in a novel mouse model of the human disease,Tuberous Sclerosis, involving conditional inactivation of the Tsc1 gene specifically in glia and have implicated abnormalities of astrocyte glutamate transporters and potassium channels as candidate mechanisms for epileptogenesis.
The second major area of research involves seizure-induced brain injury, including both lethal (neuronal cell death) and non-lethal mechanisms of cell injury. We have studied different pharmacological models of non-convulsive status epilepticus and compared differences in seizure-induced neuronal death in these models, as assayed by conventional histological and novel fluorescent markers of cell death. A newer avenue of investigation involves directly visualizing non-lethal effects of seizures on dendrite spine structure and motility, using time-lapse two-photon imaging of live neurons in slices and in vivo during seizures. Mechanisms of seizure-induced injury to dendrites and spines related to modulation of the actin cytoskeleton have been investigated.
Selected Publications:
Zeng LH, Xu L, Rensing NR, Sinatra PM, Rothman SM, Wong M. Kainate seizures cause acute dendritic injury and actin depolymerization in vivo. J Neurosci 2007 27:11604-11613.
Ouyang Y, Wong M, Capani F, Rensing N, Lee CS, Liu Q, Martone ME, Wu J, Ellisman MH, Yamada K, Choi DW. A transient decrease in F-actin may be necessary for translocation of proteins into dendritic spines. Eur J Neurosci 2005 22:2995-3005.
Rensing NR, Ouyang Y, Yang XF, Yamada KA, Rothman SM, Wong M. In vivo imaging of dendritic spines during electrographic seizures. Ann Neurol 2005 58:888-898.
Wong M, Ess KE, Uhlmann EJ, Jansen LA, Li W, Crino PB, Mennerick S, Yamada KA, Gutmann DH. Impaired astrocyte glutamate transport in a mouse epilepsy model of tuberous sclerosis complex. Ann Neurol 2003 54:251-256.
Wang Q, Bardgett ME, Wong M, Wozniak DF, Lou J, McNeil BD, Chen C, Nardi A, Reid DC, Yamada KA, Ornitz DM. Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron 2002 35:25-38.
Last Updated: 10/31/2007 |