title: Intrinsic excitability changes induced by acute treatment of hippocampal CA1 pyramidal neurons with exogenous amyloid β peptide.
abstract: Accumulation of beta-amyloid (Aβ) peptides in the human brain is a canonical pathological hallmark of Alzheimer's disease (AD). Recent work in Aβ-overexpressing transgenic mice indicates that increased brain Aβ levels can be associated with aberrant epileptiform activity. In line with this, such mice can also exhibit altered intrinsic excitability (IE) of cortical and hippocampal neurons: these observations may relate to the increased prevalence of seizures in AD patients. In this study, we examined what changes in IE are produced in hippocampal CA1 pyramidal cells after 2-5 h treatment with an oligomeric preparation of synthetic human Aβ 1-42 peptide. Whole cell current clamp recordings were compared between Aβ-(500 nM) and vehicle-(DMSO 0.05%) treated hippocampal slices obtained from mice. The soluble Aβ treatment did not produce alterations in sub-threshold intrinsic properties, including membrane potential, input resistance, and hyperpolarization activated "sag". Similarly, no changes were noted in the firing profile evoked by 500 ms square current supra-threshold stimuli. However, Aβ 500 nM treatment resulted in the hyperpolarization of the action potential (AP) threshold. In addition, treatment with Aβ at 500 nM depressed the after-hyperpolarization that followed both a single AP or 50 Hz trains of a number of APs between 5 and 25. These data suggest that acute exposure to soluble Aβ oligomers affects IE properties of CA1 pyramidal neurons differently from outcomes seen in transgenic models of amyloidopathy. However, in both chronic and acute models, the IE changes are toward hyperexcitability, reinforcing the idea that amyloidopathy and increased incidence in seizures might be causally related in AD patients.
authors.affiliation: Medical School, University of Exeter, Hatherly Building, Streatham Campus, Exeter, EX4 4PS, United Kingdom.|School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Tamagnini
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Scullion
authors.affiliation: Medical School, University of Exeter, Hatherly Building, Streatham Campus, Exeter, EX4 4PS, United Kingdom.|School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom.
authors.forename: Jon T
authors.initials: JT
authors.lastname: Brown
authors.affiliation: Medical School, University of Exeter, Hatherly Building, Streatham Campus, Exeter, EX4 4PS, United Kingdom.|School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol, BS8 1TD, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Randall
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D056547:CA1 Region, Hippocampal / Q000166:cytology*; D004558:Electric Stimulation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; amyloidopathy; hippocampus; hyperexcitability; membrane properties