title: Optogenetics enables functional analysis of human embryonic stem cell-derived grafts in a Parkinson's disease model.
abstract: Recent studies have shown evidence of behavioral recovery after transplantation of human pluripotent stem cell (PSC)-derived neural cells in animal models of neurological disease. However, little is known about the mechanisms underlying graft function. Here we use optogenetics to modulate in real time electrophysiological and neurochemical properties of mesencephalic dopaminergic (mesDA) neurons derived from human embryonic stem cells (hESCs). In mice that had recovered from lesion-induced Parkinsonian motor deficits, light-induced selective silencing of graft activity rapidly and reversibly re-introduced the motor deficits. The re-introduction of motor deficits was prevented by the dopamine agonist apomorphine. These results suggest that functionality depends on graft neuronal activity and dopamine release. Combining optogenetics, slice electrophysiology and pharmacological approaches, we further show that mesDA-rich grafts modulate host glutamatergic synaptic transmission onto striatal medium spiny neurons in a manner reminiscent of endogenous mesDA neurons. Thus, application of optogenetics in cell therapy can link transplantation, animal behavior and postmortem analysis to enable the identification of mechanisms that drive recovery.
authors.affiliation: 1] Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, New York, USA. [2] Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, New York, USA.
authors.forename: Julius A
authors.initials: JA
authors.lastname: Steinbeck
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Se Joon
authors.initials: SJ
authors.lastname: Choi
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Mrejeru
authors.affiliation: 1] Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, New York, USA. [2] Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, New York, USA.
authors.forename: Yosif
authors.initials: Y
authors.lastname: Ganat
authors.affiliation: 1] Department of Bioengineering, Stanford University, Stanford, California, USA. [2] Department of Psychiatry, Stanford University, Stanford, California, USA. [3] Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.affiliation: 1] Department of Neurology, Columbia University Medical Center, New York, New York, USA. [2] Department of Psychiatry, Columbia University Medical Center, New York, New York, USA. [3] Department of Pharmacology, Columbia University Medical Center, New York, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Mosharov
authors.affiliation: 1] Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, New York, USA. [2] Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, New York, USA.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000166:cytology / Q000637:transplantation*; D000066449:Human Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D008636:Mesencephalon / Q000166:cytology / Q000637:transplantation; D051379:Mice; D058953:Neural Stem Cells / Q000637:transplantation; D062308:Optogenetics / Q000379:methods*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009435:Synaptic Transmission / Q000235:genetics