Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model

Pascal E. Sanchez, Lei Zhu, Laure Verret, Keith A. Vossel, Anna G. Orr, John R. Cirrito, Nino Devidze, Kaitlyn Ho, Gui Qiu Yu, Jorge J. Palop, Lennart Mucke

Research output: Contribution to journalArticle

334 Scopus citations

Abstract

In light of the rising prevalence of Alzheimer's disease (AD), new strategies to prevent, halt, and reverse this condition are needed urgently. Perturbations of brain network activity are observed in AD patients and in conditions that increase the risk of developing AD, suggesting that aberrant network activity might contribute to AD-related cognitive decline. Human amyloid precursor protein (hAPP) transgenic mice simulate key aspects of AD, including pathologically elevated levels of amyloid-β peptides in brain, aberrant neural network activity, remodeling of hippocampal circuits, synaptic deficits, and behavioral abnormalities. Whether these alterations are linked in a causal chain remains unknown. To explore whether hAPP/amyloid-β-induced aberrant network activity contributes to synaptic and cognitive deficits, we treated hAPP mice with different antiepileptic drugs. Among the drugs tested, only levetiracetam (LEV) effectively reduced abnormal spike activity detected by electroencephalography. Chronic treatment with LEV also reversed hippocampal remodeling, behavioral abnormalities, synaptic dysfunction, and deficits in learning and memory in hAPP mice. Our findings support the hypothesis that aberrant network activity contributes causally to synaptic and cognitive deficits in hAPP mice. LEV might also help ameliorate related abnormalities in people who have or are at risk for AD.

Original languageEnglish
Pages (from-to)E2895-E2903
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number42
DOIs
StatePublished - Oct 16 2012

Keywords

  • Dementia
  • Epilepsy
  • Hyperexcitability
  • Plasticity
  • Therapy

Fingerprint Dive into the research topics of 'Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model'. Together they form a unique fingerprint.

  • Cite this