Ultrasonic Neuromodulation via Astrocytic TRPA1

Low-intensity, low-frequency ultrasound (LILFU) is the next-generation, non-invasive brain stimulation technology for treating various neurological and psychiatric disorders. However, the underlying cellular and molecular mechanism of LILFU-induced neuromodulation has remained unknown. Here, we report that LILFU-induced neuromodulation is initiated by opening of TRPA1 channels in astrocytes. The Ca2+ entry through TRPA1 causes a release of gliotransmitters including glutamate through Best1 channels in astrocytes. The released glutamate activates NMDA receptors in neighboring neurons to elicit action potential firing. Our results reveal an unprecedented mechanism of LILFU-induced neuromodulation, involving TRPA1 as a unique sensor for LILFU and glutamate-releasing Best1 as a mediator of glia-neuron interaction. These discoveries should prove to be useful for optimization of human brain stimulation and ultrasonogenetic manipulations of TRPA1. [Display omitted] •Ultrasound-induced neuromodulation is initiated by opening of TRPA1 in astrocytes•The Ca2+ entry through TRPA1 causes a release of glutamate through Best1 channels•The released glutamate activates NMDA receptors in neighboring neurons Oh et al. show that TRPA1 is the molecular sensor and transducer for low-intensity, low-frequency ultrasound (LILFU). With TRPA1’s unique co-localization and cooperation with the glutamate-releasing Ca2+-activated Best1 at the microdomains of astrocytes, LILFU is capable of eliciting neuromodulation as a consequence of neuronal NMDAR activation.