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Published on: August 17, 2021
Long-term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy
Jana Desloovere1, Paul Boon1, Lars E Larsen1,2
14Brain, Department of Neurology, Ghent University, Ghent, Belgium.
Objective:
More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy.
Methods:
Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored.
Results:
Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals.
Significance:
This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.
Insights
Chemogenetics using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) effectively suppressed temporal lobe epilepsy seizures in mice. This novel therapy offers sustained seizure control with minimal side effects.
Area of Science:
- Neuroscience
- Epilepsy Research
- Pharmacology
Background:
- Over one-third of temporal lobe epilepsy (TLE) patients experience persistent seizures despite antiepileptic drugs.
- Many TLE patients suffer severe drug-related side effects, highlighting the need for alternative treatments.
- Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) offer cell-type-specific neuronal excitability modulation.
Purpose of the Study:
- To evaluate the efficacy of chemogenetic suppression of hippocampal neurons in a mouse model of TLE.
- To assess the impact of DREADD-mediated inhibition on spontaneous seizures, EEG power, and fast ripples.
- To investigate the potential of DREADD technology for developing novel epilepsy therapies.
Main Methods:
- Intrahippocampal injection of adeno-associated viral vectors encoding inhibitory DREADD hM4Di in IHKA mice.
- Systemic administration of clozapine-N-oxide (CNO) and clozapine at various doses.
- Evaluation of seizure activity, hippocampal EEG, fast ripples, and open field behavior.
Main Results:
- DREADD-expressing mice showed robust suppression of hippocampal seizures for over 15 hours post-treatment with CNO or clozapine.
- Significant reductions in total EEG power and fast ripple occurrence were observed.
- Repeated clozapine administration led to near-complete seizure suppression in DREADD-expressing animals.
Conclusions:
- Chemogenetics provides a potent and sustainable method for suppressing spontaneous epileptic seizures.
- This approach enables targeted modulation of specific cell types within seizure networks.
- DREADD-based therapy holds promise for a new class of epilepsy treatments with reduced side effects.
