Date of Award

January 2015

Document Type


Degree Name

Doctor of Philosophy (PhD)


Biomedical Sciences

First Advisor

Saobo Lei


Temporal lobe epilepsy (TLE) is characterized by hyperexcitability of limbic structures. The entorhinal cortex (EC) is involved in the initiation and maintenance of TLE. Layers II and III of the EC in particular are hyperexcitable and are more susceptible to epileptogenesis. TLE is influenced in a complex manner by the stress-released epileptogenic neuropeptide, corticotropin-releasing factor or hormone (CRF/CRH). Nevertheless, the action site and underlying mechanisms of CRF in epilepsy are not fully understood. Here we found that the EC expresses high levels of CRF and CRF2 receptors without the expression of CRF1 receptors. CRF increased the frequency of picrotoxin (PTX)-induced epileptiform activity via CRF2 receptors and requires cyclic AMP (cAMP). However, application of selective protein kinase A (PKA) inhibitors reduced, not completely blocked CRF-induced enhancement of epileptiform activity suggesting that PKA is only partially required. Furthermore, endogenously released CRF is also involved in the epileptogenesis.

Among various ionic conductances maintaining neuronal excitability, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and the conducting current Ih has strongly been implicated in TLE. Whereas, layer III of the EC shows preferential neuronal loss in TLE, layer II is spared and becomes hyperexcitable. Since the stellate neurons of layer II express high levels of HCN channels, we investigated the role of HCN channels in CRF- mediated facilitation of epileptiform activity. In the

presence of HCN-channel blocker-ZD7288, CRF failed to increase the frequency of epileptiform activity but still augmented the numbers of synchronizing events within an epileptiform activity and the duration of epileptiform activity. This suggests that part of the effects of CRF on epilepsy is mediated via HCN channels. Furthermore, using perforated patch clamp recordings we found that CRF increased Ih recorded from layer II stellate neurons via activation of CRF2 receptors. cAMP, not PKA was responsible for CRF-mediated facilitation of Ih. At the cellular level, CRF depolarized the membrane potential resulting in increase in neuronal excitability and action potential firing. These mechanisms facilitate an increase in epileptiform activity mediated by CRF, in the EC. Our results provide a novel cellular and molecular mechanism whereby CRF modulates epilepsy.