Formation of New Inhibitory Circuits for Treating Temporal Lobe Epilepsy

Take Home Message: Stem Cell Transplants induce structural plasticity after transplantation into the Hippocampus. Structural and functional changes may be the mechanism for seizure suppression in Temporal Lobe Epilepsy Presentation: 40:29 NOTE: PowerPoint slides for presentation are located at bottom of this page

Cortical GABAergic Interneuron/Progenitor Transplantation as a Novel Therapy for Intractable Epilepsy

Epilepsy is a severe neurological disease affecting more than 70 million people worldwide that is characterized by unpredictable and abnormal electrical discharges resulting in recurrent seizures. Although antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment for seizure control, about one third of patients with epilepsy suffer from intractable seizures that are unresponsive to AEDs. Furthermore, the patients that respond to AEDs typically experience adverse systemic side effects, underscoring the urgent need to develop new therapies that target epileptic foci rather than more systemic interventions. Neurosurgical removal of affected brain tissues or implanting neurostimulator devices are effective options only for a fraction of patients with drug-refractory seizures, so it is imperative to develop treatments that are more generally applicable and restorative in nature. Considering the abnormalities of GABAergic inhibitory interneurons in epileptic brain tissues, one strategy with considerable promise is to restore normal circuit function by transplanting GABAergic interneurons/progenitors into the seizure focus. In this review, we focus on recent studies of cortical GABAergic interneuron transplantation to treat epilepsy and discuss critical issues in moving this promising experimental therapeutic treatment into clinic

GABAergic Synapse Dysfunction and Repair in Temporal Lobe Epilepsy

Severe medial temporal lobe epilepsy (mTLE) is often associated with pharmacoresistant seizures, impaired memory and mood disorders. In the hippocampus, GABAergic inhibitory interneuron dysfunction and other neural circuit abnormalities contribute to hyperexcitability, but the mechanisms are still not well understood. Experimental approaches aimed at correcting deficits in hippocampal circuits in mTLE include attempts to replace GABAergic interneurons through neural stem cell transplantation. Evidence from studies in rodent mTLE models indicates that transplanted GABAergic progenitor cells integrate into the hippocampus, form inhibitory synapses, reduce seizures and improve cognitive deficits. Here, we review current work in this field and describe potential molecular mechanisms underlying successful transplantation

CXCL12-Mediated Guidance of Migrating Embryonic Stem Cell-Derived Neural Progenitors Transplanted into the Hippocampus

Stem cell therapies for neurodegenerative disorders require accurate delivery of the transplanted cells to the sites of damage. Numerous studies have established that fluid injections to the hippocampus can induce lesions in the dentate gyrus (DG) that lead to cell death within the upper blade. Using a mouse model of temporal lobe epilepsy, we previously observed that embryonic stem cell-derived neural progenitors (ESNPs) survive and differentiate within the granule cell layer after stereotaxic delivery to the DG, replacing the endogenous cells of the upper blade. To investigate the mechanisms for ESNP migration and repair in the DG, we examined the role of the chemokine CXCL12 in mice subjected to kainic acid-induced seizures. We now show that ESNPs transplanted into the DG show extensive migration through the upper blade, along the septotemporal axis of the hippocampus. Seizures upregulate CXCL12 and infusion of the CXCR4 antagonist AMD3100 by osmotic minipump attenuated ESNP migration. We also demonstrate that seizures promote the differentiation of transplanted ESNPs toward neuronal rather than astrocyte fates. These findings suggest that ESNPs transplanted into the adult rodent hippocampus migrate in response to cytokine-mediated signals

Cortical GABAergic Interneuron/Progenitor Transplantation as a Novel Therapy for Intractable Epilepsy

Epilepsy is a severe neurological disease affecting more than 70 million people worldwide that is characterized by unpredictable and abnormal electrical discharges resulting in recurrent seizures. Although antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment for seizure control, about one third of patients with epilepsy suffer from intractable seizures that are unresponsive to AEDs. Furthermore, the patients that respond to AEDs typically experience adverse systemic side effects, underscoring the urgent need to develop new therapies that target epileptic foci rather than more systemic interventions. Neurosurgical removal of affected brain tissues or implanting neurostimulator devices are effective options only for a fraction of patients with drug-refractory seizures, so it is imperative to develop treatments that are more generally applicable and restorative in nature. Considering the abnormalities of GABAergic inhibitory interneurons in epileptic brain tissues, one strategy with considerable promise is to restore normal circuit function by transplanting GABAergic interneurons/progenitors into the seizure focus. In this review, we focus on recent studies of cortical GABAergic interneuron transplantation to treat epilepsy and discuss critical issues in moving this promising experimental therapeutic treatment into clinic