Human Stem Cell-Derived GABAergic Interneurons Establish Efferent Synapses onto Host Neurons in Rat Epileptic Hippocampus and Inhibit Spontaneous Recurrent Seizures.

Eliška Waloschková,My Andersson,Marco Ledri,Ana Gonzalez-Ramos,Jan Kudláček,Merab Kokaia,Apostolos Mikroulis

doi:10.3390/ijms222413243

Eliška Waloschková, My Andersson + Show 5 more

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https://doi.org/10.3390/ijms222413243

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Abstract

Epilepsy is a complex disorder affecting the central nervous system and is characterised by spontaneously recurring seizures (SRSs). Epileptic patients undergo symptomatic pharmacological treatments, however, in 30% of cases, they are ineffective, mostly in patients with temporal lobe epilepsy. Therefore, there is a need for developing novel treatment strategies. Transplantation of cells releasing γ-aminobutyric acid (GABA) could be used to counteract the imbalance between excitation and inhibition within epileptic neuronal networks. We generated GABAergic interneuron precursors from human embryonic stem cells (hESCs) and grafted them in the hippocampi of rats developing chronic SRSs after kainic acid-induced status epilepticus. Using whole-cell patch-clamp recordings, we characterised the maturation of the grafted cells into functional GABAergic interneurons in the host brain, and we confirmed the presence of functional inhibitory synaptic connections from grafted cells onto the host neurons. Moreover, optogenetic stimulation of grafted hESC-derived interneurons reduced the rate of epileptiform discharges in vitro. We also observed decreased SRS frequency and total time spent in SRSs in these animals in vivo as compared to non-grafted controls. These data represent a proof-of-concept that hESC-derived GABAergic neurons can exert a therapeutic effect on epileptic animals presumably through establishing inhibitory synapses with host neurons.

Highlights

Epilepsy is a neurological disorder affecting around 50 million people worldwide [1].Patients suffering from epilepsy have access to a variety of symptomatic pharmacological treatments [2,3,4,5]
We demonstrated that the human embryonic stem cells (hESCs)-derived GABAergic interneurons can functionally mature and form inhibitory synapses onto the host cells in the hippocampus already at three months and more prominently at six months post-transplantation (PT)
We demonstrate that the transplanted hESC-derived GABAergic neurons mature and integrate into the epileptic rat hippocampal network by forming afferent and efferent synaptic connections with the host cells

Summary

Introduction

Epilepsy is a neurological disorder affecting around 50 million people worldwide [1].Patients suffering from epilepsy have access to a variety of symptomatic pharmacological treatments [2,3,4,5]. Long-term intake of ASMs is associated with adverse side effects [7,8,9], and most importantly, available medications are not effective in 30% of patients who become drug-resistant [10,11] Most commonly these patients suffer from temporal lobe epilepsy (TLE), which is characterised by focal spontaneous recurrent seizures (SRSs) originating in the mesial temporal lobe often with secondary generalization. Many TLE patients exhibit comorbidities, such as depression, anxiety, psychosis, and impairment of learning and memory [12] For some of these drug-resistant patients, surgical resection of the epileptogenic focus may be an effective treatment, this therapeutic approach is possible only in a relatively small number of individuals due to the location of the seizure focus in, e.g., eloquent brain areas [13]

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