The Contribution of Nrg1/ErbB4 Signaling to the Homeostatic Effects of Seizures in Epilepsy Models

​​Temporal lobe epilepsy (TLE) is known to be induced by seizures themselves, although there is much to learn about the mechanisms by which TLE develops and progresses (“epileptogenesis”). Briefly inhibiting BDNF/TrkB signaling induces regression of epileptogenesis, yet this only occurs when introduced following a seizure. Thus, we propose that seizures also activate signaling pathways that inhibit epileptogenesis. The receptor tyrosine kinase ErbB4 is expressed exclusively in the interneurons of the hippocampus where the activation and inhibition of ErbB4 signaling exerts anti- and pro- convulsant effects respectively in diverse seizure models. We hypothesize Nrg1 activated ErbB4 to be involved in this seizure-activated, anti-epileptogenic signaling pathway. Kainic-acid status epilepticus mice cohorts and PBS control mice cohorts were studied using in situ hybridization techniques such as RNAscope to label targeted mRNA sequences with fluorescent tags. Charting the spatial profile of KA-SE induced Nrg1/ErbB4 signaling was achieved using ImageJ software that produced image based, semi-quantitative analyses of the RNAscope data. We expect to be able to quantify and localize the increases in Nrg1 mRNA expression that has been seen in our preliminary data. Considering that ErbB4 receptors are expressed in hippocampal interneurons together with the requirement of parvalbumin (PV) interneurons for the anticonvulsant effects of Nrg1 suggested that seizures may enhance PV neuron mediated synaptic inhibition. Understanding the circuits and cells in which KA-SE activates Nrg1/ErbB4 signaling would facilitate elucidating its functional consequences.