Optogenetic Modulation of Limbic Circuity in a Pig Seizure Model
Abstract number :
1.162
Submission category :
2. Translational Research / 2B. Devices, Technologies, Stem Cells
Year :
2025
Submission ID :
469
Source :
www.aesnet.org
Presentation date :
12/6/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Filip Mivalt, PhD – Mayo Clinic Rochester
Daniela Maltais, BS – Mayo Clinic
Karni Lev Bar-Or, BS – Modulight Bio
Yoav Kfir, PhD – Modulight Bio
Jiwon Kim, BS – Mayo Clinic Rochester
Inyong Kim, Ph.D. – Mayo Clinic Rochester
Matan Hershko, MS – Modulight Bio
Vaclav Kremen, PhD – Mayo Clinic
Ofir Levi, PhD – Modulight Bio
Ofer Yizhar, PhD – Weizmann Institute of Science
Yotam Eldar, MD – Modulight Bio
Su-youne Chang, Ph.D. – Mayo Clinic Rochester
Gregory Worrel, MD,PhD – Mayo Clinics
Rationale: Mesial temporal lobe epilepsy (mTLE) is a common drug-resistant focal epilepsy and is associated with sleep, memory, and mood comorbidities. Deep brain stimulation and responsive neurostimulation are established electrical neuromodulation therapies for refractory epilepsy. However, complete seizure freedom is rare and electrical brain stimulating therapies can induce off-target stimulation-related side effects. eOPN3 is a red-shifted, inhibitory type-2 opsin (GPCR) that enables cell-type-specific neuromodulation with the potential for precision control of complex epilepsy networks. We evaluate a technology platform for modulation of limbic circuitry in pigs to advance translational applications of integrated electrical and optogenetic therapy.
Methods: An optogenetic construct (AAV5/9-CaMKII-eOPN3-mScarlet; AAV titer: 2x1012 > particles/µl) with MRI contrast (Gadolinium) was stereotactically delivered into the bilateral hippocampus (HPC) and anterior nucleus of the thalamus (ANT) in 3 Göttingen micropigs. Post-surgical MRI imaging confirmed targeting accuracy. An acute experiment was performed two to three months later with four electrodes and optrodes placed in the ANT and HPC. The local field potentials (LFPs) were recorded at baseline and during stimulation for Single Pulse Electrical Potentials (SPEP) characterization of the ANT-HPC network. Stereotactically infused Kainic Acid (KA) was utilized to induce acute focal seizures in the HPC to study the inhibitory effect of eOPN3 on seizures. Fiber photometry and histopathology was performed to confirm eOPN3 expression during and after the acute study.
Results: Combined opto-electric experiments were performed to demonstrate suppression of synaptic transmission through the Gi/o signaling pathway in the HPC-ANT network. Fiberphotometry demonstrated expression of the viral construct throughout HPC and ANT. The ANT-HPC SPEPs were utilized to demonstrate functional connectivity suppression with light illumination. The LFP beta band (12 Hz – 30 Hz) HPC power and ANT-HPC SPEPs were suppressed with HPC illumination in all three subjects (LFP-Suppression - Baseline: 0.05 ± 0.22 µV2/Hz, Light: -0.16 ± 0.25 µV2/Hz, p< 0.0001; SPEP-Suppression -
Translational Research