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Comparison of epilepsy mouse models induced by kainic acid through different administration routes
Li-Wei Xing1, Chen Yang1, Wenxuan Tang1
1Institute for Translational Brain Research, Center for Clinical Neuro-AI, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Joint International Research Laboratory of Sleep, Fudan University, Shanghai 200032, China.
Abstract:
Sleep disruption associated with epilepsy is frequently observed in clinical practice. Various epilepsy animal models including the widely-used chemoconvulsant kainic acid (KA) have been developed to unveil the mechanisms underlying this life-threatening central disorder and improve sleep management. However, a systematic comparison of epilepsy models induced through different KA administration routes (intrahippocampal, IH, vs. intraperitoneal, IP) remains lacking. In this study, we monitored the dynamic changes of sleep/wake architecture, the development of epilepsy, and performed histological mapping of brain regions potentially implicated in epileptogenesis. We observed a more severe disruption of sleep architecture associated with seizures perpetuating for a longer time in the IHKA group. IHKA induced a more robust epilepsy pattern with significant increases of wakefulness and reductions of sleep during the acute phase. A chronic epilepsy model was developed in the IHKA group, but not in the IPKA group. Both IHKA and IPKA groups developed NREM sleep fragmentation during the chronic phase. Isolated spikes induced by IHKA appeared more frequently than those induced by IPKA at all time points, and gradually declined before stabilization around day 14 post-administration. Both IPKA and IHKA induced elevated c-Fos expression within 3 h after the drug administration as compared to their controls. Pearson correlation analyses of c-Fos expression across brain regions revealed that the IHKA group exhibited more correlations among multiple brain regions, reflecting a broader network of activated regions compared with the IPKA group after local KA exposure. Therefore, IHKA creates a more robust epilepsy mouse model characterized by a more fragmented sleep pattern, more seizures, and more isolated spikes.
Insights
Intrahippocampal kainic acid (IHKA) creates a more robust epilepsy model than intraperitoneal kainic acid (IPKA), leading to severe sleep disruption, prolonged seizures, and broader brain region activation.
Area of Science:
- Neuroscience
- Sleep Medicine
- Epilepsy Research
Background:
- Sleep disruption is common in epilepsy patients.
- Kainic acid (KA) models are used to study epilepsy and sleep disturbances.
- A comparison of different KA administration routes for epilepsy modeling is needed.
Purpose of the Study:
- To systematically compare intrahippocampal (IHKA) and intraperitoneal (IPKA) kainic acid administration routes in an epilepsy mouse model.
- To evaluate the impact on sleep/wake architecture, seizure development, and brain region activation.
Main Methods:
- Monitoring sleep/wake architecture in mice after IHKA or IPKA administration.
- Assessing seizure activity and epilepsy development over time.
- Histological mapping of brain regions and c-Fos expression analysis.
Main Results:
- IHKA induced more severe sleep disruption, prolonged seizures, and a chronic epilepsy model compared to IPKA.
- IHKA showed increased wakefulness and decreased sleep during the acute phase.
- Both groups exhibited NREM sleep fragmentation, but IHKA had more frequent isolated spikes and broader c-Fos expression correlation networks.
Conclusions:
- Intrahippocampal kainic acid administration provides a more robust epilepsy model with significant sleep fragmentation and broader neural network involvement.
- This model is valuable for studying the complex relationship between epilepsy and sleep disturbances.
