Date of Award

1-1-2010

Document Type

Campus Access Dissertation

Department

Biomedical Science

First Advisor

David D Mott

Abstract

Temporal lobe epilepsy (TLE) is a debilitating neurological condition characterized by spontaneous recurrent seizures and associated comorbidities. Examining alterations in synaptic plasticity can give us insight into the epileptogenic phenotype as well as accompanying conditions like cognitive decline and psychosis that may be observed in subjects with TLE. We decided to investigate changes in long term potentiation (LTP), a cellular correlate of learning and memory during acute epileptiform activity and in chronic epilepsy.

LTP in the adult brain is regulated by numerous neuromodulators and one of them is the neuropeptide neuregulin (NRG). In the hippocampus, NRG is released in an activity-dependant manner and acts via ErbB4 tyrosine kinases to release dopamine (DA). In the sham condition, activation of NRG/ErbB4 signaling causes DA release which acts on D4 dopaminergic receptors (DARs) to block LTP. Similarly, application of an ErbB4 antagonist enhances LTP suggesting that NRG/ErbB4 signaling is an important constitutive modulator of plasticity in the adult hippocampus.

Using the high potassium bursting model of acute seizures in rat hippocampal slices, we found that NRG application blocked burst-induced potentiation and allowed a subsequent train to produce LTP. Next, to observe the actions of NRG in chronic TLE we induced status epilepticus (SE) in rats and performed hippocampal brain slice electrophysiology. We discovered that activation of NRG signaling blocks LTP in the sham condition, but enables LTP in epilepsy. This represents a basic alteration in the epileptic circuit as to how synaptic plasticity is regulated. Since effects of NRG/ErbB4 activation are via the DAergic system, we used specific DAR agonists and antagonists to examine further this shift in NRG function. We observed differential activation of DARs in epilepsy such that NRG acts through D4 DARs in the sham condition but through D1/D5 DARs in epilepsy.

Thus, we found that NRG/ErbB4 signaling regulates synaptic plasticity differently in epilepsy indicating that it may be an attractive therapeutic target for seizures and comorbidities in TLE. Finally, we suggest that plasticity in the diseased neuronal circuit is modulated by conditions very much unlike those in the non-diseased brain.

Rights

© 2010, Sloka Sampathkumar Iyengar

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