title: Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer's disease mouse model.
abstract: BACKGROUND
  Recent studies have shown that several strains of transgenic Alzheimer's disease (AD) mice overexpressing the amyloid precursor protein (APP) have cortical hyperexcitability, and their results have suggested that this aberrant network activity may be a mechanism by which amyloid-β (Aβ) causes more widespread neuronal dysfunction. Specific anticonvulsant therapy reverses memory impairments in various transgenic mouse strains, but it is not known whether reduction of epileptiform activity might serve as a surrogate marker of drug efficacy for memory improvement in AD mouse models.
  
  
  METHODS
  Transgenic AD mice (APP/PS1 and 3xTg-AD) were chronically implanted with dural electroencephalography electrodes, and epileptiform activity was correlated with spatial memory function and transgene-specific pathology. The antiepileptic drugs ethosuximide and brivaracetam were tested for their ability to suppress epileptiform activity and to reverse memory impairments and synapse loss in APP/PS1 mice.
  
  
  RESULTS
  We report that in two transgenic mouse models of AD (APP/PS1 and 3xTg-AD), the presence of spike-wave discharges (SWDs) correlated with impairments in spatial memory. Both ethosuximide and brivaracetam reduce mouse SWDs, but only brivaracetam reverses memory impairments in APP/PS1 mice.
  
  
  CONCLUSIONS
  Our data confirm an intriguing therapeutic role of anticonvulsant drugs targeting synaptic vesicle protein 2A across AD mouse models. Chronic ethosuximide dosing did not reverse spatial memory impairments in APP/PS1 mice, despite reduction of SWDs. Our data indicate that SWDs are not a reliable surrogate marker of appropriate target engagement for reversal of memory dysfunction in APP/PS1 mice.
authors.affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA ; Division of Neurology, The University of British Columbia, Djavad Mowafaghian Centre for Brain Health, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z3 Canada.
authors.forename: Haakon B
authors.initials: HB
authors.lastname: Nygaard
authors.affiliation: Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Kaufman
authors.affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sekine-Konno
authors.affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Division of Pediatric Neurology, The University of British Columbia, British Columbia Children's Hospital, 4480 Oak Street, Vancouver, BC V6H 3V4 Canada.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Huh
authors.affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA.
authors.forename: Hilary
authors.initials: H
authors.lastname: Going
authors.affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Feldman
authors.affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kostylev
authors.affiliation: Department of Neurology, Yale University School of Medicine, 800 Howard Avenue, New Haven, CT 06510 USA ; Cellular Neuroscience, Neurodegeneration, and Repair Program (CNNR), Yale University School of Medicine, 295 Congress Avenue, New Haven, CT 06536 USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter