Chemogenetics with PSAM4-GlyR decreases excitability and epileptiform activity in epileptic hippocampus
Ana Gonzalez-Ramos1,2, Fredrik Berglind3, Jan Kudláček3,4
1Epilepsy Center, Department of Clinical Sciences, Lund University Hospital, Lund, Sweden. agonzalez@broadinstitute.org.
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 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.
Insights
Chemogenetics targeting specific neurons offers a promising "on-demand" treatment for drug-resistant epilepsy. The PSAM/PSEM system shows potential in reducing seizure activity, though further research is needed.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Drug-resistant epilepsy affects one-third of patients, remaining a significant clinical challenge.
- Gene therapy and chemogenetics show promise for targeted epilepsy treatment by modulating neuronal activity.
- The PSAM/PSEM system offers a specific chemogenetic approach for potential clinical application.
Purpose of the Study:
- To evaluate the PSAM/PSEM chemogenetic system for treating drug-resistant epilepsy.
- To assess the efficacy of the inert ligand uPSEM817 in activating the PSAM4-GlyR channel.
- To investigate the anti-seizure potential of this targeted chemogenetic therapy in vitro, ex vivo, and in vivo models.
Main Methods:
- In vitro electrophysiology to measure action potentials and membrane resistance.
- Organotypic slice cultures to assess spontaneous epileptiform activity.
- In vivo electrographic seizure monitoring in a mouse model of temporal lobe epilepsy.
Main Results:
- uPSEM817 selectively activated PSAM4-GlyR, reducing depolarization-induced action potentials in vitro by shunting currents.
- In organotypic slices, uPSEM817 decreased bursts and peak amplitude of epileptiform activity.
- In vivo, uPSEM817 showed a trend towards reducing interictal discharges but did not significantly alter electrographic seizures.
Conclusions:
- PSAM4-GlyR-based chemogenetics demonstrates potential as an anti-seizure strategy for drug-resistant epilepsy.
- The PSAM/PSEM system provides a targeted, on-demand therapeutic approach.
- Further optimization is required to enhance the in vivo efficacy of this chemogenetic therapy.
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