title: Pam heterozygous mice reveal essential role for Cu in amygdalar behavioral and synaptic function.
abstract: Copper (Cu) is an essential element with many biological roles, but its roles in the mammalian nervous system are poorly understood. Mice deficient in the cuproenzyme peptidylglycine α-amidating monooxygenase (Pam(+/-) mice) were initially generated to study neuropeptide amidation. Pam(+/-) mice exhibit profound deficits in a few behavioral tasks, including enhancements in innate fear along with deficits in acquired fear. Interestingly, several Pam(+/-) phenotypes were recapitulated in Cu-restricted wild-type mice and rescued in Cu-supplemented Pam(+/-) mice. These behaviors correspond to enhanced excitability and deficient synaptic plasticity in the amygdala of Pam(+/-) mice, which are also rescued by Cu supplementation. Cu and ATP7A are present at synapses, in key positions to respond to and influence synaptic activity. Further study demonstrated that extracellular Cu is necessary for wild-type synaptic plasticity and sufficient to induce long-term potentiation. These experiments support roles for PAM in Cu homeostasis and for synaptic Cu in amygdalar function.
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Gaier
authors.forename: Betty A
authors.initials: BA
authors.lastname: Eipper
authors.forename: Richard E
authors.initials: RE
authors.lastname: Mains
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000679:Amygdala / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D027682:Cation Transport Proteins / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D019587:Dietary Supplements; D005239:Fear / Q000502:physiology*; D018756:GABA Antagonists / Q000494:pharmacology; D006579:Heterozygote; D006706:Homeostasis; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D010433:Pentylenetetrazole / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced; D013569:Synapses / Q000378:metabolism
chemical_list: C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D018756:GABA Antagonists; D009097:Multienzyme Complexes; D003300:Copper; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; D010433:Pentylenetetrazole
keywords: ATP7A; amygdala; copper; fear conditioning; peptidylglycine α-amidating monooxygenase; synaptic plasticity