Graduate and Postdoctoral Studies
Novel Mechanisms for Magnetogenetic Neuromodulation
Thursday, April 27, 2017
to 12:00 PM
1042 Duncan Hall
Magnetogenetic tools permit wireless stimulation of specific neurons located deep inside the brain of freely moving animals: A capability that improves the study of neural activity and its correlation to behavior. Recent reports have shown a fully genetically encoded, magnetically sensitive chimera consisting of ferritin and TRPV4 that can elicit action potentials in neurons when exposed to a magnetic field. The iron-sequestering protein, ferritin serves as the magnetically sensitive domain in this chimera, while TRPV4 is a cation selective channel that responds to mechanical and temperature stimuli. While it was suggested that the mode of operation was through mechanical stimulation of the channel by ferritin, later calculations show that the forces exerted by ferritin nanoparticles are orders of magnitude lower than what is required for channel gating.
We propose two alternate mechanisms that are based on thermally mediated pathways for how paramagnetic ferritin could gate the thermally sensitive TRPV4. The first approach is based on the magnetocaloric effect wherein a magnetic field induces a change in the entropy of the ferritin nanoparticles resulting in a change in temperature that in turn gates the thermoreceptor. The second approach links the channel's mechanical and temperature responses using a simple thermodynamic model. Although the force due to ferritin is not enough to independently pull a channel open, it is still capable of doing work that results in a slight shift in the channel open probability, and in turn in an increased influx of ions over time. We support our theory with calculations and experimental data that demonstrate that the observed responses are indeed thermally mediated. In addition to reconciling biological observations with physical properties of genetically encoded magnetic nanoparticles, our explanation will also aid the design of new magnetogenetic tools with improved magnetic sensitivity.