Magnetogenetics: remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor

Abstract

Current neuromodulation techniques such as optogenetics and deep-brain stimulation are transforming basic and translational neuroscience. These two neuromodulation approaches are, however, invasive since surgical implantation of an optical fiber or wire electrode is required. Here, we have invented a non-invasive magnetogenetics that combines the genetic targeting of a magnetoreceptor with remote magnetic stimulation. The non-invasive activation of neurons was achieved by neuronal expression of an exogenous magnetoreceptor, an iron-sulfur cluster assembly protein 1 (Isca1). In HEK-293 cells and cultured hippocampal neurons expressing this magnetoreceptor, application of an external magnetic field resulted in membrane depolarization and calcium influx in a reproducible and reversible manner, as indicated by the ultrasensitive fluorescent calcium indicator GCaMP6s. Moreover, the magnetogenetic control of neuronal activity might be dependent on the direction of the magnetic field and exhibits on-response and off-response patterns for the external magnetic field applied. The activation of this magnetoreceptor can depolarize neurons and elicit trains of action potentials, which can be triggered repetitively with a remote magnetic field in whole-cell patch-clamp recording. In transgenic Caenorhabditis elegans expressing this magnetoreceptor in myo-3-specific muscle cells or mec-4-specific neurons, application of the external magnetic field triggered muscle contraction and withdrawal behavior of the worms, indicative of magnet-dependent activation of muscle cells and touch receptor neurons, respectively. The advantages of magnetogenetics over optogenetics are its exclusive non-invasive, deep penetration, long-term continuous dosing, unlimited accessibility, spatial uniformity and relative safety. Like optogenetics that has gone through decade-long improvements, magnetogenetics, with continuous modification and maturation, will reshape the current landscape of neuromodulation toolboxes and will have a broad range of applications to basic and translational neuroscience as well as other biological sciences. We envision a new age of magnetogenetics is coming.Electronic supplementary materialThe online version of this article (doi:10.1007/s11434-015-0902-0) contains supplementary material, which is available to authorized users.

Thermal Transients Excite Neurons through Universal Intramembrane Mechanoelectrical Effects

“…Also, the identified mechanoelectrical effects are dominant in the short time scales considered here, but in conjunction with parallel thermal effects like changes in the Q 10 factor [47], probably play a significant role under a wide array of thermal modulation scenarios [48]. Related insights may also help guide our understanding of other emerging neurophysical modalities like magnetogenetic stimulation (whose biophysics is still poorly understood [49,50]). For example, we note that membrane mechanoelectrical effects involving dimensional changes were suggested in other contexts involving changes in intramembranal forces, including action potential-related intramembrane thickness variations [51][52][53] and ultrasoundinduced formation of intramembrane cavities (or "bilayer sonophores" [54]).…”

Identification of medaka magnetoreceptor and cryptochromes

“…Besides, Xie's group has reported the co-purification of MAGR and CRY2 in human (Qin et al, 2016). Therefore, using medaka as a vertebrate model for magnet biology will not only boost our knowledge of animal MR but also cast light on understanding human MR. On the other hand, magnetogenetics that combine the genetic targeting of MagR with remote magnetic stimulation has been developed as a promising method for non-invasive neuron stimulation, which might replace the invasive approaches such as optogenetics and deep-brain stimulation in neurobiology research (Long et al, 2015). Thus, our study of medaka magnet biology could provide a good model and help advance the technology of magnetogenetics.…”

“…For example, in neuroscience, magnetogenetics was recently reported as a promising noninvasive technique to control gene expression and cellular activity in vivo (Etoc et al, 2013;Etoc et al, 2015;Long et al, 2015;Stanley et al, 2015;Stanley et al, 2016;Wheeler et al, 2016). It shows many advantages over the currently widely used techniques such as deep-brain stimulation and optogenetics (Wichmann and Delong, 2006;Zhang et al, 2011), which require surgical implantation of a wire electrode or optical fiber (Kringelbach et al, 2007;Häusser, 2014).…”

“…It shows many advantages over the currently widely used techniques such as deep-brain stimulation and optogenetics (Wichmann and Delong, 2006;Zhang et al, 2011), which require surgical implantation of a wire electrode or optical fiber (Kringelbach et al, 2007;Häusser, 2014). More importantly, the technique that combines the genetic targeting of MagR with remote magnetic stimulation has been reported (Long et al, 2015). The study of MR will provide a solid basis for this emerging and promising technique.…”

Molecular tools for acute spatiotemporal manipulation of signal transduction

“…Recent work has demonstrated that overexpressing the protein ferritin allows for the intracellular synthesis of magnetic nanoparticles; when ferritin is fused to a TRPV channel, the resulting particles allow for radio and magnetic activation of that channel [55,56]. In addition, the recent discovery of a new candidate magnetoreceptor MagR, an iron-sulfur cluster-binding protein that creates a rodlike complex with the cryptochrome Cry, motivates the possibility of a new family of fully genetically-encoded magnetogenetic tools [57, 58]. …”