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Human stem cell‐derived gabaergic interneurons establish efferent synapses onto host neurons in rat epileptic hippocampus and inhibit spontaneous recurrent seizures

Waloschková, Eliška LU ; Gonzalez‐ramos, Ana LU ; Mikroulis, Apostolos LU ; Kudláček, Jan LU ; Andersson, My LU orcid ; Ledri, Marco LU and Kokaia, Merab LU (2021) In International Journal of Molecular Sciences 22(24).
Abstract

Epilepsy is a complex disorder affecting the central nervous system and is characterised by spontaneously recurring seizures (SRSs). Epileptic patients undergo symptomatic pharmacolog-ical 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 ex-citation 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... (More)

Epilepsy is a complex disorder affecting the central nervous system and is characterised by spontaneously recurring seizures (SRSs). Epileptic patients undergo symptomatic pharmacolog-ical 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 ex-citation 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 inter-neurons 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.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cell integration, Epilepsy, GABA, Human embryonic stem cells, Interneurons, Optogenetics, Synaptic integration
in
International Journal of Molecular Sciences
volume
22
issue
24
article number
13243
publisher
MDPI AG
external identifiers
  • scopus:85120695922
  • pmid:34948040
ISSN
1661-6596
DOI
10.3390/ijms222413243
language
English
LU publication?
yes
id
41f5a271-69a5-4826-acad-2a764d39775a
date added to LUP
2022-01-25 12:03:53
date last changed
2024-06-17 03:03:01
@article{41f5a271-69a5-4826-acad-2a764d39775a,
  abstract     = {{<p>Epilepsy is a complex disorder affecting the central nervous system and is characterised by spontaneously recurring seizures (SRSs). Epileptic patients undergo symptomatic pharmacolog-ical 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 ex-citation 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 inter-neurons 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.</p>}},
  author       = {{Waloschková, Eliška and Gonzalez‐ramos, Ana and Mikroulis, Apostolos and Kudláček, Jan and Andersson, My and Ledri, Marco and Kokaia, Merab}},
  issn         = {{1661-6596}},
  keywords     = {{Cell integration; Epilepsy; GABA; Human embryonic stem cells; Interneurons; Optogenetics; Synaptic integration}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{24}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Human stem cell‐derived gabaergic interneurons establish efferent synapses onto host neurons in rat epileptic hippocampus and inhibit spontaneous recurrent seizures}},
  url          = {{http://dx.doi.org/10.3390/ijms222413243}},
  doi          = {{10.3390/ijms222413243}},
  volume       = {{22}},
  year         = {{2021}},
}