title: Soluble Aβ oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance.
abstract: Epileptic activity may be more prevalent in early stage Alzheimer's disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aβ accumulation. The mechanism by which Aβ-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials (fEPSP) in stratum radiatum and population spikes (PSs) in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Aβ oligomers (oAβ) blocked hippocampal LTP and EPSP-spike (E-S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAβ elevated glutamate levels in the hippocampal slice medium. Recording the PS revealed that oAβ increased PS frequency and reduced LTP, and this LTP deficit was occluded by pretreatment with the GABAA antagonist picrotoxin. Whole-cell recordings showed that oAβ significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAβ impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAβ. We conclude that soluble Aβ oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity.
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Huixin
authors.initials: H
authors.lastname: Xu
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zhangyuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tiernan T
authors.initials: TT
authors.lastname: O'Malley
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dainan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangdong 510120, China. Electronic address: pingyixu@sina.com.
authors.forename: Pingyi
authors.initials: P
authors.lastname: Xu
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: sli11@partners.org.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Li
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D016466:CHO Cells; D003412:Cricetulus; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000927:Anticonvulsants; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
keywords: Alzheimer's disease; Aβ oligomers; Epileptiform activity; Longterm potentiation; Population spike; Synaptic plasticity