Microcircuit formation following transplantation of mouse embryonic stem cell-derived neurons in peripheral nerve.
Motoneurons derived from embryonic stem cells can be transplanted in the tibial nerve, where they extend axons to functionally innervate target muscle. Here, we studied spontaneous muscle contractions in these grafts 3 mo following transplantation. One-half of the transplanted grafts generated rhythmic muscle contractions of variable patterns, either spontaneously or in response to brief electrical stimulation. Activity generated by transplanted embryonic stem cell-derived neurons was driven by glutamate and was modulated by muscarinic and GABAergic/glycinergic transmission. Furthermore, rhythmicity was promoted by the same transmitter combination that evokes rhythmic locomotor activity in spinal cord circuits. These results demonstrate that there is a degree of self-assembly of microcircuits in these peripheral grafts involving embryonic stem cell-derived motoneurons and interneurons. Such spontaneous activity is reminiscent of embryonic circuit development in which spontaneous activity is essential for proper connectivity and function and may be necessary for the grafts to form functional connections with muscle.NEW & NOTEWORTHYThis manuscript demonstrates that, following peripheral transplantation of neurons derived from embryonic stem cells, the grafts are spontaneously active. The activity is produced and modulated by a number of transmitter systems, indicating that there is a degree of self-assembly of circuits in the grafts.
Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Surgery (Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada.
Philippe
P
Magown
Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Medicine (Neurology), Dalhousie University, Halifax, Nova Scotia, Canada; and.
Victor F
VF
Rafuse
Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada; r.brownstone@ucl.ac.uk.|Department of Surgery (Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada.|Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, United Kingdom.
Robert M
0000-0001-5135-2725
RM
Brownstone
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000502:physiology*; D000066450:Mouse Embryonic Stem Cells / Q000502:physiology* / Q000637:transplantation; D018482:Muscle, Skeletal / Q000294:innervation; D009415:Nerve Net / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D059348:Peripheral Nerve Injuries / Q000601:surgery*
D018377:Neurotransmitter Agents
central pattern generator; embryonic stem cell-derived motoneurons; locomotion; peripheral nerve injury