Temporal lobe epilepsy (TLE) is a devastating type of seizure disorder that is difficult to control with existing antiepileptic drugs. In order to better understand the process of epileptogenesis and to develop innovative therapeutic approaches for the management of TLE, animal models have been developed that exhibit the hallmarks of this seizure disorder: an initial insult to the CNS, a variable latent period, and the eventual development of spontaneous seizures of temporal lobe origin. The overall goal of this proposal is to determine the role of the medial entorhinal cortex (mEC) in the development of chronic epilepsy in the kainic acid model of TLE. This proposal will test the hypothesis that altered circuitry and changes in excitatory synaptic function of neurons in the superficial layers of the mEC contribute, at least in part, to hyperexcitability and synchronization in the mEC-hippocampal (HC) neural circuit in the kainic acid model of TLE. This hypothesis will be tested by using the whole cell patch clamp technique in the combined mEC-HC brain slice preparation obtained from control rats and those subjected to the kainic acid-induced status epilepticus (SE) model of TLE (Aims 2 & 3) to perform the following specific aims: 1) Compare and contrast the kinetics, short-term plasticity, and pharmacological modulation of excitatory postsynaptic currents (EPSCs) in Layer III PYR cells and Layer II STEL cells of the mEC in brain slices obtained from normal animals. 2) Determine if there are progressive changes in the electroresponsive membrane properties of STEL cells in the mEC at various time points following kainate-induced SE. Determine if there are alterations in the kinetics, short-term plasticity, and pharmacological modulation of EPSCs in Layer II STEL cells as a function of time following kainate-induced SE. 3) Determine if there is an enhanced probability of monosynaptic connections between STEL cells following KA treatment. By surveying the development of functional changes in principle neurons of the mEC in an animal model of TLE, we will gain insight into why PYR cells degenerate, why STEL cells become hyperexcitable, and what the functional impact of these changes are for the mEC-HC circuit. These experiments will set the stage for the development of future therapeutic interventions for the treatment of pharmacoresistant epilepsy. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Schools of Pharmacy
Salt Lake City
United States
Zip Code
Vargas, Jay R; Takahashi, D Koji; Thomson, Kyle E et al. (2013) The expression of kainate receptor subunits in hippocampal astrocytes after experimentally induced status epilepticus. J Neuropathol Exp Neurol 72:919-32
Alex, Anitha B; Saunders, Gerald W; Dalpé-Charron, Alexandre et al. (2011) CGX-1007 prevents excitotoxic cell death via actions at multiple types of NMDA receptors. Neurotoxicology 32:392-9
Takahashi, D K; Vargas, J R; Wilcox, K S (2010) Increased coupling and altered glutamate transport currents in astrocytes following kainic-acid-induced status epilepticus. Neurobiol Dis 40:573-85
Otto, James F; Singh, Nanda A; Dahle, E Jill et al. (2009) Electroconvulsive seizure thresholds and kindling acquisition rates are altered in mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions. Epilepsia 50:1752-9
Singh, Nanda A; Otto, James F; Dahle, E Jill et al. (2008) Mouse models of human KCNQ2 and KCNQ3 mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization. J Physiol 586:3405-23
Smith, Misty D; Saunders, Gerald W; Clausen, Rasmus P et al. (2008) Inhibition of the betaine-GABA transporter (mGAT2/BGT-1) modulates spontaneous electrographic bursting in the medial entorhinal cortex (mEC). Epilepsy Res 79:6-13
West, P J; Dalpe-Charron, A; Wilcox, K S (2007) Differential contribution of kainate receptors to excitatory postsynaptic currents in superficial layer neurons of the rat medial entorhinal cortex. Neuroscience 146:1000-12
Smith, Misty D; Adams, Amy C; Saunders, Gerald W et al. (2007) Phenytoin- and carbamazepine-resistant spontaneous bursting in rat entorhinal cortex is blocked by retigabine in vitro. Epilepsy Res 74:97-106