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.