Nonsurgical Control of Seizure Threshold with Acoustically Targeted Chemogenetics

Many neurological and psychiatric diseases are characterized by pathological neuronal activity. Current treatments involve drugs, surgeries, and implantable devices to modulate or remove the affected region. However, none of these methods can be simultaneously nonsurgical and possess site- and cell type specificity. Here, we apply a nonsurgical neuromodulation approach called Acoustically-Targeted Chemogenetics, or ATAC, to increase the seizure threshold. The ATAC approach used a multipoint focused ultrasound to transiently open the blood-brain barrier of the whole hippocampus (HPC) and transduce pyramidal neurons with engineered G-protein-coupled receptors to inhibit their activity. To express the engineered receptors in the mouse HPC, we used a recently engineered viral vector optimized for ultrasound-based gene delivery to the brain, AAV.FUS.3. In a mouse fluorothyl seizure model, we showed successful gene delivery throughout the HPC, a significant neuronal activity inhibition as evidenced by an increase in seizure threshold. Finally, we benchmarked these effects against a clinically prescribed drug that acts without spatial precision.