Persisting neurobehavioral effects of developmental copper exposure in wildtype and metallothionein 1 and 2 knockout mice.
Metallothioneins (MT) are small proteins, which are crucial for the distribution of heavy and transition metals. Previously, we found in mice that knockout of MT 1 and 2 genes (MTKO) impaired spatial learning and potentiated the learning impairment caused by developmental mercury exposure. The current study examined the neurocognitive and neurochemical effects of MTKO with the developmental copper (Cu) supplementation.



Wildtype (WT) and MTKO mice were given supplemental Cu (0, 10 or 50 mg/l) in their drinking water during gestation and until weaning. When the mice were young adults they were trained on the win-shift 8-arm radial maze test of spatial learning and memory. After cognitive testing, their brains were analyzed for norepinepherine, dopamine and serotonin levels.



In the spatial learning test, wildtype mice showed the normal sex difference with males performing more accurately than the females. This effect was eliminated by MTKO and restored by moderate Cu supplementation during development. In neurochemical studies, MTKO caused a significant overall increase in serotonin in all of the regions studied: the frontal cortex, posterior cortex, hippocampus, striatum, midbrain, and brainstem. MTKO also caused a significant increase in norepinepherine in the brainstem and hippocampus. In wildtype mice, Cu supplementation during development caused a significant decline in dopamine and norepinepherine in the midbrain and dopamine in the frontal cortex. These effects were blocked by MTKO.



The normal sex difference in spatial working memory accuracy, which was eliminated by MTKO, was restored by moderate copper supplementation. MTKO increased serotonin across all brain areas studied and increased norepinepherine only in the hippocampus and brainstem. MTKO blocked copper-induced decreases in dopamine and norepinepherine in the midbrain and dopamine in the frontal cortex.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box #104790, Durham, NC, 27710, USA.
Ann
A
Petro
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box #104790, Durham, NC, 27710, USA.
Hannah G
HG
Sexton
Department of Neurology, Weill Cornell Medical College, Cornell University, New York, NY, USA.
Caroline
C
Miranda
Department of Radiology, University of Florida College of Medicine, Gainesville, FL, USA.
Anit
A
Rastogi
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
Jonathan H
JH
Freedman
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box #104790, Durham, NC, 27710, USA. edlevin@duke.edu.
Edward D
ED
Levin
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D003300:Copper / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D008668:Metallothionein / Q000172:deficiency*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout
D003300:Copper; D008668:Metallothionein
Copper; Developmental; Dopamine; Memory; Metallothionein; Mouse; Norepinephrine; Radial-arm maze; Serotonin