Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice
Background: Mesial temporal lobe epilepsy (MTLE) is a prevalent form of focal epilepsy characterized by seizures originating from the hippocampus and adjacent regions. Neurostimulation presents an alternative for surgery-ineligible patients with intractable seizures. However, conventional approaches...
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Elsevier
2025-08-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125001810 |
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| author | Piret Kleis Enya Paschen Andrea Djie-Maletz Andreas Vlachos Carola A. Haas Ute Häussler |
| author_facet | Piret Kleis Enya Paschen Andrea Djie-Maletz Andreas Vlachos Carola A. Haas Ute Häussler |
| author_sort | Piret Kleis |
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| description | Background: Mesial temporal lobe epilepsy (MTLE) is a prevalent form of focal epilepsy characterized by seizures originating from the hippocampus and adjacent regions. Neurostimulation presents an alternative for surgery-ineligible patients with intractable seizures. However, conventional approaches have limited efficacy and require refinement for better seizure control. While hippocampal low-frequency stimulation (LFS) has shown promising seizure reduction in animal studies and small clinical cohorts, its mechanisms, sex-specific outcomes, and long-term effects remain unknown. Objectives: We aimed to identify the antiepileptic and cognitive outcomes and potential underlying mechanisms of long-term hippocampal LFS in chronically epileptic male and female mice. Methods: We used the intrahippocampal kainate mouse model replicating the features of MTLE: spontaneous seizures, hippocampal sclerosis, and memory deficits. During the chronic phase of epilepsy, we applied 1 Hz electrical LFS in the sclerotic hippocampus 6 h/day, four times/week for 5 weeks and examined its effects on epileptiform activity, spatial memory, and kainate-induced pathological features at cellular and synaptic levels. Results: Long-term hippocampal LFS consistently diminished focal seizures in epileptic male and female mice, with seizure reduction extending beyond the stimulation period. Additionally, long-term LFS relieved spatial memory deficits and reversed pathological modifications at perforant path-dentate granule cell synapses shortly after stimulation. LFS had no significant effect on secondarily generalized seizures, anxiety-like behaviour, neurogenesis, hippocampal sclerosis, or presynaptic vesicles in perforant path fibres. Conclusion: These findings provide clinically relevant insights into the seizure type-specific effects of hippocampal LFS, which, alongside synaptic and behavioural improvements, could contribute to enhanced seizure control and quality of life in MTLE patients. |
| format | Article |
| id | doaj-art-2b6199d01e0b4a3f8d74b1ec15a69eb6 |
| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-2b6199d01e0b4a3f8d74b1ec15a69eb62025-08-20T01:52:55ZengElsevierNeurobiology of Disease1095-953X2025-08-0121210696510.1016/j.nbd.2025.106965Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic micePiret Kleis0Enya Paschen1Andrea Djie-Maletz2Andreas Vlachos3Carola A. Haas4Ute Häussler5Experimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; Corresponding authors at: Experimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Breisacher Str. 64, 79106 Freiburg, Germany.Experimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, GermanyExperimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, GermanyDepartment of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; BrainLinks-BrainTools Center, University of Freiburg, Freiburg, GermanyExperimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany; BrainLinks-BrainTools Center, University of Freiburg, Freiburg, GermanyExperimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany; BrainLinks-BrainTools Center, University of Freiburg, Freiburg, Germany; Corresponding authors at: Experimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Breisacher Str. 64, 79106 Freiburg, Germany.Background: Mesial temporal lobe epilepsy (MTLE) is a prevalent form of focal epilepsy characterized by seizures originating from the hippocampus and adjacent regions. Neurostimulation presents an alternative for surgery-ineligible patients with intractable seizures. However, conventional approaches have limited efficacy and require refinement for better seizure control. While hippocampal low-frequency stimulation (LFS) has shown promising seizure reduction in animal studies and small clinical cohorts, its mechanisms, sex-specific outcomes, and long-term effects remain unknown. Objectives: We aimed to identify the antiepileptic and cognitive outcomes and potential underlying mechanisms of long-term hippocampal LFS in chronically epileptic male and female mice. Methods: We used the intrahippocampal kainate mouse model replicating the features of MTLE: spontaneous seizures, hippocampal sclerosis, and memory deficits. During the chronic phase of epilepsy, we applied 1 Hz electrical LFS in the sclerotic hippocampus 6 h/day, four times/week for 5 weeks and examined its effects on epileptiform activity, spatial memory, and kainate-induced pathological features at cellular and synaptic levels. Results: Long-term hippocampal LFS consistently diminished focal seizures in epileptic male and female mice, with seizure reduction extending beyond the stimulation period. Additionally, long-term LFS relieved spatial memory deficits and reversed pathological modifications at perforant path-dentate granule cell synapses shortly after stimulation. LFS had no significant effect on secondarily generalized seizures, anxiety-like behaviour, neurogenesis, hippocampal sclerosis, or presynaptic vesicles in perforant path fibres. Conclusion: These findings provide clinically relevant insights into the seizure type-specific effects of hippocampal LFS, which, alongside synaptic and behavioural improvements, could contribute to enhanced seizure control and quality of life in MTLE patients.http://www.sciencedirect.com/science/article/pii/S0969996125001810NeurostimulationDentate gyrusHippocampal sclerosisKainateStructural plasticitySpatial navigation |
| spellingShingle | Piret Kleis Enya Paschen Andrea Djie-Maletz Andreas Vlachos Carola A. Haas Ute Häussler Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice Neurobiology of Disease Neurostimulation Dentate gyrus Hippocampal sclerosis Kainate Structural plasticity Spatial navigation |
| title | Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice |
| title_full | Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice |
| title_fullStr | Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice |
| title_full_unstemmed | Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice |
| title_short | Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice |
| title_sort | long term hippocampal low frequency stimulation alleviates focal seizures memory deficits and synaptic pathology in epileptic mice |
| topic | Neurostimulation Dentate gyrus Hippocampal sclerosis Kainate Structural plasticity Spatial navigation |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125001810 |
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