title: In vivo and in vitro analyses of amygdalar function reveal a role for copper.
abstract: Mice with a single copy of the peptide amidating monooxygenase (Pam) gene (PAM(+/-)) are impaired in contextual and cued fear conditioning. These abnormalities coincide with deficient long-term potentiation (LTP) at excitatory thalamic afferent synapses onto pyramidal neurons in the lateral amygdala. Slice recordings from PAM(+/-) mice identified an increase in GABAergic tone (Gaier ED, Rodriguiz RM, Ma XM, Sivaramakrishnan S, Bousquet-Moore D, Wetsel WC, Eipper BA, Mains RE. J Neurosci 30: 13656-13669, 2010). Biochemical data indicate a tissue-specific deficit in Cu content in the amygdala; amygdalar expression of Atox-1 and Atp7a, essential for transport of Cu into the secretory pathway, is reduced in PAM(+/-) mice. When PAM(+/-) mice were fed a diet supplemented with Cu, the impairments in fear conditioning were reversed, and LTP was normalized in amygdala slice recordings. A role for endogenous Cu in amygdalar LTP was established by the inhibitory effect of a brief incubation of wild-type slices with bathocuproine disulfonate, a highly selective, cell-impermeant Cu chelator. Interestingly, bath-applied CuSO₄ had no effect on excitatory currents but reversibly potentiated the disynaptic inhibitory current. Bath-applied CuSO₄ was sufficient to potentiate wild-type amygdala afferent synapses. The ability of dietary Cu to affect signaling in pathways that govern fear-based behaviors supports an essential physiological role for Cu in amygdalar function at both the synaptic and behavioral levels. This work is relevant to neurological and psychiatric disorders in which disturbed Cu homeostasis could contribute to altered synaptic transmission, including Wilson's, Menkes, Alzheimer's, and prion-related diseases.
authors.affiliation: Neuroscience Department, University of Connecticut Health Center, Farmington, Connecticut;
authors.forename: E D
authors.initials: ED
authors.lastname: Gaier
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina;
authors.forename: R M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina;
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon;
authors.forename: M
authors.initials: M
authors.lastname: Ralle
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina; Department of Neurobiology, Duke University Medical Center, Durham, North Carolina; and Department of Cell Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: W C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Neuroscience Department, University of Connecticut Health Center, Farmington, Connecticut;
authors.forename: B A
authors.initials: BA
authors.lastname: Eipper
authors.affiliation: Neuroscience Department, University of Connecticut Health Center, Farmington, Connecticut; mains@uchc.edu.
authors.forename: R E
authors.initials: RE
authors.lastname: Mains
mesh_terms: D000679:Amygdala / Q000502:physiology*; D000818:Animals; D003213:Conditioning, Psychological / Q000502:physiology; D003300:Copper / Q000008:administration & dosage / Q000378:metabolism*; D004032:Diet; D005239:Fear / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009433:Neural Inhibition / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000502:physiology; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission; D013788:Thalamus / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: D009097:Multienzyme Complexes; D003300:Copper; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase
keywords: GABA; fear; learning and memory; peptidylglycine alpha-amidating monooxygenase; synaptic plasticity