This project concerns the role of ectopic dentate granule cells in temporal lobe epilepsy. The dentate gyrus is believed to act as a gatekeeper or filter to inhibit the propagation of synchronized discharge through the limbic circuit. In both temporal lobe epilepsy and the pilocarpine model of temporal lobe epilepsy, granule cell neurogenesis, aberrant granule cell migration, and mossy fiber sprouting create a reverberating network that can reduce the threshold for granule cell synchronization and potentially diminish the normally high resistance of the dentate gyrus to seizure propagation. Pilocarpine-treated rats will be used to investigate one aspect of the novel granule cell network: namely, the properties and potential pathophysiological role of hilar ectopic granule cells. Many of the new granule cells produced as a result of seizures migrate aberrantly into the dentate hilus. Many hilar ectopic granule cells, unlike ather granule cells in either normal or epileptic brain, burst spontaneously at resting membrane potential. Preliminary data suggest that these cells also have little spike frequency adaptation, a high ratio of excitatory to inhibitory innervation, a relatively low resting membrane potential, and high input resistance. Their cellular morphology predicts the existence of abundant pathways by which the hyperactivity of these cells can be transmitted to the rest of the granule cell population. We will determine to what extent the hyperexcitable properties of hilar ectopiC granule cells can be attributed to enhanced T -type calcium current, enhanced BK-type calcium-dependent potassium current, and/or reduced SK-type calcium-dependent potassium current. The potential role of hilar ectopic granule cells in epileptiform activity will be assessed by physically removing them from hippocampal slices, by correlating the number of these cells with population activity, and by pharmacological means. Neurons that generate a high-frequency burst of action potentials as their minimal response to threshold stimulation are considered of central importance to the generation and propagation of epileptiform activity. Because hilar ectopic granule cells meet this criterion, they may be critical to seizure propagation through the dentate gyrus in epileptic brain. Pharmacotherapy of temporal lobe epilepsy usually fails to achieve long-term remission. This project will shed light on the pathophysiological role of an anatomical reorganization unique to this disorder and may uncover novel therapeutic targets. In particular, it may be advantageous to target mechanisms of hyperexcitability operative in hilar ectopic granule cells, but not in normal granule cells. .
Many of the new dentate granule cells produced as a result of seizures migrate aberrantly into the hilus. Most of these hilar ectopic granule cells fire action potentials and cellular bursts spontaneously. The insertion of spontaneously bursting neurons into the normally quiescent dentate gyrus circuitry may contribute to the breakdown of this region's filtering function, thereby facilitating seizure propagation. If so, then novel therapies for temporal lobe epilepsy might target mechanisms of hyperexcitability operative in ectopic granule cells, but not in normal granule cells.
| Qiu, Mei Hong; Chen, Michael C; Fuller, Patrick M et al. (2016) Stimulation of the Pontine Parabrachial Nucleus Promotes Wakefulness via Extra-thalamic Forebrain Circuit Nodes. Curr Biol 26:2301-12 |
| Cameron, Michael C; Zhan, Ren-Zhi; Nadler, J Victor (2011) Morphologic integration of hilar ectopic granule cells into dentate gyrus circuitry in the pilocarpine model of temporal lobe epilepsy. J Comp Neurol 519:2175-92 |
| Zhan, Ren-Zhi; Timofeeva, Olga; Nadler, J Victor (2010) High ratio of synaptic excitation to synaptic inhibition in hilar ectopic granule cells of pilocarpine-treated rats. J Neurophysiol 104:3293-304 |
