Mitochondrial superoxide contributes to hippocampal synaptic dysfunction and memory deficits in Angelman syndrome model mice

Emanuela Santini, Kathryn L. Turner, Xakila B. Ramaraj, Michael P. Murphy, Eric Klann, Xhanoch Kaphzan

Research output: Contribution to journalArticle

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 hippo campal pathophysiology in AS model mice and that targeting mitochondrial ROS pharmacologically could benefit individuals with AS.

Original languageEnglish (US)
Pages (from-to)16213-16220
Number of pages8
JournalJournal of Neuroscience
Volume35
Issue number49
DOIs
StatePublished - Dec 9 2015

Fingerprint

Angelman Syndrome
Memory Disorders
Superoxides
Neuronal Plasticity
Reactive Oxygen Species
Mitochondria
Oxidative Stress
Language Development Disorders
Chromosomes, Human, Pair 15
Ligases
Ubiquitin
Neurodegenerative Diseases
Proteolysis
Genes
Fear
Epilepsy
Hippocampus
Antioxidants
Alleles
Mothers

Keywords

  • Hippocampus
  • Memory
  • Mitochondria
  • Neurodevelopmental disorders
  • Oxidative stress
  • Synpatic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mitochondrial superoxide contributes to hippocampal synaptic dysfunction and memory deficits in Angelman syndrome model mice. / Santini, Emanuela; Turner, Kathryn L.; Ramaraj, Xakila B.; Murphy, Michael P.; Klann, Eric; Kaphzan, Xhanoch.

In: Journal of Neuroscience, Vol. 35, No. 49, 09.12.2015, p. 16213-16220.

Research output: Contribution to journalArticle

Santini, Emanuela ; Turner, Kathryn L. ; Ramaraj, Xakila B. ; Murphy, Michael P. ; Klann, Eric ; Kaphzan, Xhanoch. / Mitochondrial superoxide contributes to hippocampal synaptic dysfunction and memory deficits in Angelman syndrome model mice. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 49. pp. 16213-16220.
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