title: Altered intrinsic neuronal excitability and reduced Na+ currents in a mouse model of Alzheimer's disease.
abstract: Transgenic mice that overproduce beta-amyloid (Aβ) peptides can exhibit central nervous system network hyperactivity. Patch clamp measurements from CA1 pyramidal cells of PSAPP and wild type mice were employed to investigate if altered intrinsic excitability could contribute to such network hyperfunction. At approximately 10 months, when PSAPP mice have a substantial central nervous system Aβ load, resting potential and input resistance were genotype-independent. However, PSAPP mice exhibited a substantially more prominent action potential (AP) burst close to the onset of weak depolarizing current stimuli. The spike afterdepolarization (ADP) was also larger in PSAPP mice. The rate of rise, width and height of APs were reduced in PSAPP animals; AP threshold was unaltered. Voltage-clamp recordings from nucleated macropatches revealed that somatic Na(+) current density was depressed by approximately 50% in PSAPP mice. K(+) current density was unaltered. All genotype-related differences were absent in PSAPP mice aged 5-7 weeks which lack a substantial Aβ load. We conclude that intrinsic neuronal hyperexcitability and changes to AP waveforms may contribute to neurophysiological deficits that arise as a consequence of Aβ accumulation.
authors.affiliation: Pfizer Applied Neurophysiology Group, University of Bristol School of Physiology and Pharmacology, Bristol, UK.
authors.forename: Jon T
authors.initials: JT
authors.lastname: Brown
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chin
authors.forename: Steven C
authors.initials: SC
authors.lastname: Leiser
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Randall
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000503:physiopathology; D008564:Membrane Potentials / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics; D012964:Sodium / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D012964:Sodium