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Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus

Gonzalez-Ramos, Ana LU ; Berglind, Fredrik LU ; Kudláček, Jan LU ; Rocha, Elza R. ; Melin, Esbjörn LU orcid ; Sebastião, Ana M. ; Valente, Cláudia A. ; Ledri, Marco LU ; Andersson, My LU orcid and Kokaia, Merab LU (2024) In Gene Therapy
Abstract

Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an “on-demand” treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM817, which selectively... (More)

Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an “on-demand” treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM817, which selectively activates the chloride-permeable channel PSAM4-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM817 decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM817 in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM4-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.

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Contribution to journal
publication status
in press
subject
in
Gene Therapy
publisher
Springer Nature
external identifiers
  • pmid:39455855
  • scopus:85207366883
ISSN
0969-7128
DOI
10.1038/s41434-024-00493-7
language
English
LU publication?
yes
id
e5b20a68-fad6-4160-a15f-2d21b39d8d54
date added to LUP
2025-01-13 15:31:05
date last changed
2025-07-15 06:10:29
@article{e5b20a68-fad6-4160-a15f-2d21b39d8d54,
  abstract     = {{<p>Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an “on-demand” treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM<sup>817</sup>, which selectively activates the chloride-permeable channel PSAM<sup>4</sup>-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM<sup>817</sup> decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM<sup>817</sup> in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM<sup>4</sup>-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.</p>}},
  author       = {{Gonzalez-Ramos, Ana and Berglind, Fredrik and Kudláček, Jan and Rocha, Elza R. and Melin, Esbjörn and Sebastião, Ana M. and Valente, Cláudia A. and Ledri, Marco and Andersson, My and Kokaia, Merab}},
  issn         = {{0969-7128}},
  language     = {{eng}},
  publisher    = {{Springer Nature}},
  series       = {{Gene Therapy}},
  title        = {{Chemogenetics with PSAM<sup>4</sup>-GlyR decreases excitability and epileptiform activity in epileptic hippocampus}},
  url          = {{http://dx.doi.org/10.1038/s41434-024-00493-7}},
  doi          = {{10.1038/s41434-024-00493-7}},
  year         = {{2024}},
}