Development of novel stimulation tools for seizure intervention
Relevant for Research Area
A - Foundations
The project builds on
Prof. Carola Haas
Prof. Ulrich Egert
Prof. Ilka Diester
Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsies in adults. MTLE is often associated with hippocampal sclerosis (HS) comprising neuronal cell death and structural reorganization. Considering that MTLE patients are often resistant to medication, current therapy relies mainly on resection of the epileptogenic focus. Since surgical intervention carries a high risk for the affected patient, other treatment options are desperately needed. Recently, deep brain stimulation (DBS) evolved as a promising approach for seizure interference. Typically, high-frequency stimulation (HFS, 100-200 Hz) is performed in the hippocampus or the anterior thalamic nucleus to interfere with limbic seizures, assuming that electrical pulses reduce the seizure threshold by disrupting network synchronization (Li and Cook, Epilepsia, 2018). However, in MTLE with severe HS, current stimulation protocols are often not effective. It is assumed, that extensive neuronal cell loss and glial scarring (Velasco et al., Epilepsia, 2007) alter the electrical resistance in sclerotic neural tissue. This hampers the efficacy of HFS, since stimulation can only be successful when targeting a sufficiently preserved network. Therefore, patients with severe HS may require specific stimulation parameters to achieve seizure control. In fact, a small cohort study (Lim et al., Neuromodulation, 2016) pointed to the use of low-frequency stimulation (LFS). However, to systematically assess anti-ictogenic effects of LFS in relation to disease parameters, studies in translational animal models are crucial.
We successfully established the efficacy of optogenetic and electrical low-frequency stimulation (LFS) in interfering with seizure generation in a mouse model of MTLE. Specifically, we applied LFS in the sclerotic hippocampus to study the effects on spontaneous subclinical and evoked generalized seizures. We found that stimulation at 1 Hz for 1 hr resulted in an almost complete suppression of spontaneous seizures in both hippocampi. This seizure-suppressive action during daily stimulation remained stable over several weeks. Furthermore, LFS for 30 min before a pro-convulsive stimulus successfully prevented seizure generalization. Taken together, our results suggest that hippocampal LFS constitutes a promising approach for seizure control in MTLE (Paschen et al., eLife 2020).
As a next step, we tested a novel potassium channel-based optogenetic silencer, named PACK, as a tool for seizure intervention. The PACK tool has two components: a photoactivated adenylyl cyclase from Beggiatoa (bPAC) and a cAMP dependent potassium channel, SthK, which carries a large, long-lasting potassium current in mammalian cells. Previously, it has been shown that activating the PACK silencer with short light pulses led to a significant reduction of neuronal firing in various in vitro and acute in vivo settings. Here, we examined the viability of performing long-term studies in vivo by looking at the inhibitory action and side effects of PACK and its components in healthy and epileptic adult male mice. We targeted hippocampal cornu ammonis (CA1) pyramidal cells using a viral vector and enabled illumination of these neurons via an implanted optic fiber. Local field potential (LFP) recordings from the CA1 of freely moving mice revealed significantly reduced neuronal activity during 50-minute intermittent (0.1 Hz) illumination, especially in the gamma frequency range. Furthermore, we applied bPAC and PACK in the contralateral hippocampus of chronically epileptic mice following a unilateral injection of intrahippocampal kainate. Unexpectedly, the expression of bPAC in the contralateral CA1 area was sufficient to prevent the spread of spontaneous epileptiform activity from the seizure focus to the contralateral hippocampus indicating that the PACK tool is a potent optogenetic inhibitor in vivo (Kleis et al., BMC Biology 2021).
Kleis P, Paschen E, Häussler U, Bernal Sierra YA, Haas CA (2021) Long-term in vivo characterization and application of a novel potassium channel-based optogenetic silencer in the healthy and epileptic mouse hippocampus. BMC Biology (in press).