Copper is an endogenous modulator of neural circuit spontaneous activity.
For reasons that remain insufficiently understood, the brain requires among the highest levels of metals in the body for normal function. The traditional paradigm for this organ and others is that fluxes of alkali and alkaline earth metals are required for signaling, but transition metals are maintained in static, tightly bound reservoirs for metabolism and protection against oxidative stress. Here we show that copper is an endogenous modulator of spontaneous activity, a property of functional neural circuitry. Using Copper Fluor-3 (CF3), a new fluorescent Cu(+) sensor for one- and two-photon imaging, we show that neurons and neural tissue maintain basal stores of loosely bound copper that can be attenuated by chelation, which define a labile copper pool. Targeted disruption of these labile copper stores by acute chelation or genetic knockdown of the CTR1 (copper transporter 1) copper channel alters the spatiotemporal properties of spontaneous activity in developing hippocampal and retinal circuits. The data identify an essential role for copper neuronal function and suggest broader contributions of this transition metal to cell signaling.
Departments of Chemistry and.
Sheel C
SC
Dodani
Vision Sciences Graduate Program, Department of Optometry.
Alana
A
Firl
Departments of Chemistry and.
Jefferson
J
Chan
Departments of Chemistry and Howard Hughes Medical Institute, University of California, Berkeley, CA 94720.
Christine I
CI
Nam
Departments of Chemistry and.
Allegra T
AT
Aron
Departments of Chemistry and.
Carl S
CS
Onak
Departments of Chemistry and.
Karla M
KM
Ramos-Torres
Departments of Chemistry and.
Jaeho
J
Paek
Molecular and Cell Biology.
Corey M
CM
Webster
Molecular and Cell Biology, Helen Wills Neuroscience Institute, and.
Marla B
MB
Feller
Departments of Chemistry and Howard Hughes Medical Institute, University of California, Berkeley, CA 94720 Molecular and Cell Biology, Helen Wills Neuroscience Institute, and chrischang@berkeley.edu.
Christopher J
CJ
Chang
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D027682:Cation Transport Proteins / Q000172:deficiency / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology / Q000502:physiology*; D000079923:Copper Transporter 1; D004305:Dose-Response Relationship, Drug; D005260:Female; D005456:Fluorescent Dyes / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008982:Molybdenum / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D013267:Stilbenes / Q000494:pharmacology; D013329:Structure-Activity Relationship
C493989:3,4,5-trimethoxy-4'-bromo-cis-stilbene; D027682:Cation Transport Proteins; D002614:Chelating Agents; D000079923:Copper Transporter 1; D005456:Fluorescent Dyes; C490077:Slc31a1 protein, mouse; D013267:Stilbenes; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate
copper signaling; fluorescent sensor; molecular imaging; neural activity