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CA3 principal cell activation triggers hypersynchronous-onset seizures in a mouse model of mesial temporal lobe
Siyan Wang1, Maxime Lévesque1, Teddy A J Fisher1
1Department of Neurology & Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montréal, Quebec, Canada.
Abstract:
Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy and it is characterized by seizures that are often refractory to medications. Seizures in MTLE have two main patterns of onset that have been termed hypersynchronous (HYP) and low-voltage fast (LVF) and are believed to mainly depend on the activity of excitatory principal cells and inhibitory interneurons, respectively. In this study, we investigated whether unilateral open-loop optogenetic activation of CaMKII-positive principal cells in the hippocampus CA3 region favors the generation of spontaneous HYP seizures in kainic acid-treated (KA) CaMKII-ChR2 mice. Optogenetic activation of CA3 principal cells (1 Hz, 180 s ON, 220 s OFF) was implemented for 15 days after KA-induced status epilepticus. We found that both LVF and HYP seizures occurred in nonstimulated CaMKII-ChR2 (n = 6) and stimulated CaMKII-Cre (n = 5) mice. In contrast, optogenetic activation of principal cells in CaMKII-ChR2 mice (n = 5) triggered only HYP seizures that were characterized by high fast ripple (250-500 Hz) rates during the pre-ictal and ictal periods. These results provide firm evidence that in MTLE spontaneous seizures with different onset patterns depend on distinct neuronal network mechanisms of generation. They also demonstrate that HYP seizures occurring in vivo along with their associated fast ripples depend on the activity of principal cells in the CA3 region.NEW & NOTEWORTHY Previous evidence suggested that different seizure onset patterns rely on the activity of distinct neuronal populations. In this study, we show for the first time that in vivo optogenetic stimulation of CaMKII principal cells in kainic acid-treated mice triggers hypersynchronous-onset seizures that are associated with fast ripples. Our findings indicate that in patients with predominant HYP-onset seizures, anticonvulsant treatments should be aimed at limiting the firing of principal neurons in the seizure onset zone.
Insights
Optogenetic activation of principal cells in kainic acid-treated mice triggered hypersynchronous seizures, suggesting principal neuron activity drives these epilepsy events. This finding may guide treatments for hypersynchronous-onset seizures.
Area of Science:
- Neuroscience
- Epilepsy Research
- Optogenetics
Background:
- Mesial temporal lobe epilepsy (MTLE) is a common focal epilepsy, often drug-resistant.
- MTLE seizures present with hypersynchronous (HYP) or low-voltage fast (LVF) onset patterns.
- These patterns are hypothesized to involve excitatory principal cells (HYP) and inhibitory interneurons (LVF).
Purpose of the Study:
- To investigate if optogenetic activation of hippocampal CA3 principal cells promotes spontaneous HYP seizures in a mouse model of MTLE.
- To determine the role of principal cell activity in generating specific seizure onset patterns.
Main Methods:
- Utilized kainic acid (KA) to induce status epilepticus in CaMKII-ChR2 mice.
- Administered unilateral open-loop optogenetic stimulation (1 Hz, 180s ON, 220s OFF) to CA3 principal cells for 15 days post-SE.
- Recorded electroencephalographic (EEG) activity to analyze seizure occurrence and patterns (HYP/LVF) and fast ripple activity.
Main Results:
- Non-stimulated and stimulated control groups (CaMKII-ChR2, CaMKII-Cre) exhibited both LVF and HYP seizures.
- Optogenetic activation of principal cells in CaMKII-ChR2 mice specifically triggered HYP seizures.
- These optogenetically induced HYP seizures were characterized by high fast ripple rates (250-500 Hz) during pre-ictal and ictal periods.
Conclusions:
- Spontaneous seizures in MTLE with distinct onset patterns arise from different neuronal network mechanisms.
- Activity of CA3 principal cells is crucial for the in vivo generation of HYP seizures and associated fast ripples.
- Targeting principal neuron activity in the seizure onset zone may be a therapeutic strategy for HYP-onset epilepsy.
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