PMID- 27315032 OWN - NLM STAT- MEDLINE DCOM- 20170606 LR - 20220318 IS - 1531-8249 (Electronic) IS - 0364-5134 (Print) IS - 0364-5134 (Linking) VI - 80 IP - 2 DP - 2016 Aug TI - Direct current stimulation induces mGluR5-dependent neocortical plasticity. PG - 233-46 LID - 10.1002/ana.24708 [doi] AB - OBJECTIVE: To obtain insights into mechanisms mediating changes in cortical excitability induced by cathodal transcranial direct current stimulation (tDCS). METHODS: Neocortical slices were exposed to direct current stimulation (DCS) delivered through Ag/AgCl electrodes over a range of current orientations, magnitudes, and durations. DCS-induced cortical plasticity and its receptor dependency were measured as the change in layer II/III field excitatory postsynaptic potentials by a multielectrode array, both with and without neurotransmitter receptor blockers or allosteric modulators. In vivo, tDCS was delivered to intact mice scalp via surface electrodes. Molecular consequences of DCS in vitro or tDCS in vivo were tested by immunoblot of protein extracted from stimulated slices or the neocortex harvested from stimulated intact mice. RESULTS: Cathodal DCS in vitro induces a long-term depression (DCS-LTD) of excitatory synaptic strength in both human and mouse neocortical slices. DCS-LTD is abolished with an mGluR5 negative allosteric modulator, mechanistic target of rapamycin (mTOR) inhibitor, and inhibitor of protein synthesis. However, DCS-LTD persists despite either gamma-aminobutyric acid type A receptor or N-methyl-D-aspartate receptor inhibition. An mGluR5-positive allosteric modulator, in contrast, transformed transient synaptic depression resultant from brief DCS application into durable DCS-LTD. INTERPRETATION: We identify a novel molecular pathway by which tDCS modulates cortical excitability, and indicate a capacity for synergistic interaction between tDCS and pharmacologic mGluR5 facilitation. The findings support exploration of cathodal tDCS as a treatment of neurologic conditions characterized by aberrant regional cortical excitability referable to mGluR5-mTOR signaling. Ann Neurol 2016;80:233-246. CI - (c) 2016 American Neurological Association. FAU - Sun, Yan AU - Sun Y AD - Department of Neurology and F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA. AD - Neuromodulation Program, Boston Children's Hospital, Boston, MA. AD - Program in Neuroscience, Harvard Medical School, Boston, MA. FAU - Lipton, Jonathan O AU - Lipton JO AD - Department of Neurology and F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA. AD - Division of Sleep Medicine, Harvard Medical School, Boston, MA. FAU - Boyle, Lara M AU - Boyle LM AD - Department of Neurology and F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA. FAU - Madsen, Joseph R AU - Madsen JR AD - Department of Neurosurgery, Boston Children's Hospital, Boston, MA. FAU - Goldenberg, Marti C AU - Goldenberg MC AD - Department of Neurology and F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA. FAU - Pascual-Leone, Alvaro AU - Pascual-Leone A AD - Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. FAU - Sahin, Mustafa AU - Sahin M AUID- ORCID: 0000-0001-7044-2953 AD - Department of Neurology and F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA. FAU - Rotenberg, Alexander AU - Rotenberg A AD - Department of Neurology and F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA. AD - Neuromodulation Program, Boston Children's Hospital, Boston, MA. AD - Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. LA - eng GR - K08 HD071026/HD/NICHD NIH HHS/United States GR - R21 NS085491/NS/NINDS NIH HHS/United States GR - R21 NS082870/NS/NINDS NIH HHS/United States GR - R01 NS073601/NS/NINDS NIH HHS/United States GR - P30 HD018655/HD/NICHD NIH HHS/United States GR - R21 MH099196/MH/NIMH NIH HHS/United States GR - R01 HD069776/HD/NICHD NIH HHS/United States GR - U54 HD090255/HD/NICHD NIH HHS/United States GR - R01 NS088583/NS/NINDS NIH HHS/United States GR - UL1 RR025758/RR/NCRR NIH HHS/United States PT - Journal Article DEP - 20160707 PL - United States TA - Ann Neurol JT - Annals of neurology JID - 7707449 RN - 0 (2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine) RN - 0 (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide) RN - 0 (Benzamides) RN - 0 (GRM5 protein, human) RN - 0 (Imidazoles) RN - 0 (Pyrazoles) RN - 0 (Pyridines) RN - 0 (Receptor, Metabotropic Glutamate 5) RN - 76726-92-6 (2-Amino-5-phosphonovalerate) RN - 98600C0908 (Cycloheximide) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) RN - Y37615DVKC (Bicuculline) SB - IM MH - 2-Amino-5-phosphonovalerate/pharmacology MH - Animals MH - Benzamides/pharmacology MH - Bicuculline/pharmacology MH - Cycloheximide/pharmacology MH - Electric Stimulation MH - Excitatory Postsynaptic Potentials/drug effects/*physiology MH - Humans MH - Imidazoles/pharmacology MH - Long-Term Synaptic Depression/drug effects/physiology MH - Male MH - Mice MH - Neocortex/metabolism/*microbiology/*physiology MH - Neuronal Plasticity/drug effects/*physiology MH - Pyrazoles/pharmacology MH - Pyridines/pharmacology MH - Receptor, Metabotropic Glutamate 5/agonists/antagonists & inhibitors/*physiology MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/physiology MH - *Transcranial Direct Current Stimulation PMC - PMC8270112 MID - NIHMS1617431 COIS- Potential Conflicts of Interest Nothing to report. EDAT- 2016/06/18 06:00 MHDA- 2017/06/07 06:00 PMCR- 2021/07/09 CRDT- 2016/06/18 06:00 PHST- 2015/09/24 00:00 [received] PHST- 2016/06/07 00:00 [revised] PHST- 2016/06/08 00:00 [accepted] PHST- 2016/06/18 06:00 [entrez] PHST- 2016/06/18 06:00 [pubmed] PHST- 2017/06/07 06:00 [medline] PHST- 2021/07/09 00:00 [pmc-release] AID - 10.1002/ana.24708 [doi] PST - ppublish SO - Ann Neurol. 2016 Aug;80(2):233-46. doi: 10.1002/ana.24708. Epub 2016 Jul 7.