The hypothesis that adenosine plays a key role in modulating entorhinal cortex (EC) layer II neuronal excitability and that there is a greater modulation of excitability in epileptic tissue by adenosine will be tested in brain slices obtained from control rats as well from our rat model of temporal lobe epilepsy (TLE). The proposed experiments will study adenosine's ability to modulate both intrinsic and synaptically driven action potential firing in EC layer II neurons in the control and epileptic condition and investigate the mechanisms that mediate this differential modulation through two specific aims: 1. Test the hypothesis that adenosine mediated modulation of intrinsic and synaptically driven action potential firing of EC layer II neurons is altered in our rat model of TLE. 2. Test the hypothesis that adenosine receptor subtype expression patterns are altered in EC layer II neurons in our rat model of TLE. Preliminary data suggest that EC layer II neurons are hyperexcitable in our rat model of TLE as compared to control slices. Data also reveals that adenosine is able to inhibit both intrinsic and synaptically driven action potential firing in EC layer II neurons from control tissue and that concentrations of adenosine that are ineffective in modulating EC layer II neurons in control tissue are sufficient to inhibit action potential firing in EC layer II neurons from our rat model of TLE. Electrophysiological recordings will be used to examine the firing properties of these neurons and the effect that adenosine application has on the excitability of these neurons, comparing the actions between the control and TLE conditions. In situ hybridization and immunohistochemistry experiments will be carried out in order to examine the expression profile and levels of adenosine receptor subtypes in the EC in both conditions to determine the mechanism underlying the differential modulation.
This research will contribute to our understanding of TLE, specifically in regards to changes that occur in the EC, the main input area to the hippocampus. Examination of the role of adenosine in modulating excitability in this area could lead to a more effective way of inhibition seizure activity in TLE.
| Hargus, Nicholas J; Nigam, Aradhya; Bertram 3rd, Edward H et al. (2013) Evidence for a role of Nav1.6 in facilitating increases in neuronal hyperexcitability during epileptogenesis. J Neurophysiol 110:1144-57 |
| Hargus, Nicholas J; Jennings, Conor; Perez-Reyes, Edward et al. (2012) Enhanced actions of adenosine in medial entorhinal cortex layer II stellate neurons in temporal lobe epilepsy are mediated via A(1)-receptor activation. Epilepsia 53:168-76 |
| Hargus, Nicholas J; Merrick, Ellen C; Nigam, Aradhya et al. (2011) Temporal lobe epilepsy induces intrinsic alterations in Na channel gating in layer II medial entorhinal cortex neurons. Neurobiol Dis 41:361-76 |
