Bidirectional regulation of motor circuits using magnetogenetic gene therapy

Sci Adv. 2024 Oct 11;10(41):eadp9150. doi: 10.1126/sciadv.adp9150. Epub 2024 Oct 9.

Abstract

Here, we report a magnetogenetic system, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. Adeno-associated virus (AAV)-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine-2a receptor-Cre drivers resulted in motor freezing when placed in a magnetic resonance imaging machine or adjacent to a transcranial magnetic stimulation device. Functional imaging and fiber photometry confirmed activation in response to magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing Cre into the globus pallidus led to similar circuit specificity and motor responses. Last, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in the subthalamic nucleus in PitX2-Cre parkinsonian mice resulted in reduced c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits noninvasively in vivo using clinically available devices.

MeSH terms

  • Animals
  • Corpus Striatum / metabolism
  • Dependovirus* / genetics
  • Genetic Therapy* / methods
  • Genetic Vectors / genetics
  • Globus Pallidus / metabolism
  • Humans
  • Magnetic Fields
  • Mice
  • Neurons / metabolism
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Parkinson Disease / therapy
  • Receptor, Adenosine A2A / genetics
  • Receptor, Adenosine A2A / metabolism
  • Subthalamic Nucleus / metabolism
  • TRPV Cation Channels

Substances

  • TRPV1 protein, mouse
  • Receptor, Adenosine A2A
  • TRPV Cation Channels