title: Mitochondrial Superoxide Contributes to Hippocampal Synaptic Dysfunction and Memory Deficits in Angelman Syndrome Model Mice.
abstract: Angelman syndrome (AS) is a neurodevelopmental disorder associated with developmental delay, lack of speech, motor dysfunction, and epilepsy. In the majority of the patients, AS is caused by the deletion of small portions of maternal chromosome 15 harboring the UBE3A gene. This results in a lack of expression of the UBE3A gene because the paternal allele is genetically imprinted. The UBE3A gene encodes an enzyme termed ubiquitin ligase E3A (E6-AP) that targets proteins for degradation by the 26S proteasome. Because neurodegenerative disease and other neurodevelopmental disorders have been linked to oxidative stress, we asked whether mitochondrial reactive oxygen species (ROS) played a role in impaired synaptic plasticity and memory deficits exhibited by AS model mice. We discovered that AS mice have increased levels of superoxide in area CA1 of the hippocampus that is reduced by MitoQ 10-methanesuflonate (MitoQ), a mitochondria-specific antioxidant. In addition, we found that MitoQ rescued impairments in hippocampal synaptic plasticity and deficits in contextual fear memory exhibited by AS model mice. Our findings suggest that mitochondria-derived oxidative stress contributes to hippocampal pathophysiology in AS model mice and that targeting mitochondrial ROS pharmacologically could benefit individuals with AS.
  
  
  CONCLUSIONS
  Oxidative stress has been hypothesized to contribute to the pathophysiology of neurodevelopmental disorders, including autism spectrum disorders and Angelman syndrome (AS). Herein, we report that AS model mice exhibit elevated levels of mitochondria-derived reactive oxygen species in pyramidal neurons in hippocampal area CA1. Moreover, we demonstrate that the administration of MitoQ (MitoQ 10-methanesuflonate), a mitochondria-specific antioxidant, to AS model mice normalizes synaptic plasticity and restores memory. Finally, our findings suggest that antioxidants that target the mitochondria could be used therapeutically to ameliorate synaptic and cognitive deficits in individuals with AS.
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Santini
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Turner
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003.
authors.forename: Akila B
authors.identifier: http://orcid.org/0000-0001-9037-6527
authors.initials: AB
authors.lastname: Ramaraj
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge CB2 0XY, United Kingdom, and.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003, eklann@cns.nyu.edu hkaphzan@univ.haifa.ac.il.
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003, Sagol Department of Neurobiology, University of Haifa, Haifa 3498838, Israel eklann@cns.nyu.edu hkaphzan@univ.haifa.ac.il.
authors.forename: Hanoch
authors.identifier: http://orcid.org/0000-0003-4935-358X
authors.initials: H
authors.lastname: Kaphzan
mesh_terms: D000704:Analysis of Variance; D017204:Angelman Syndrome / Q000150:complications*; D000818:Animals; D003213:Conditioning, Psychological; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005239:Fear; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009043:Motor Activity / Q000502:physiology; D009069:Movement Disorders / Q000209:etiology* / Q000473:pathology*; D009943:Organophosphorus Compounds / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D009943:Organophosphorus Compounds; D013481:Superoxides; D014451:Ubiquinone; C429014:mitoquinone
keywords: hippocampus; memory; mitochondria; neurodevelopmental disorders; oxidative stress; synpatic plasticity