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. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway

“…Hyperexcitability is also detected in the brains of various AD transgenic mice36. Such aberrant increases in network excitability and compensatory inhibitory mechanisms in the hippocampus may contribute to the cognitive deficits in AD373839.…”

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

“…Supernormal production of free radicals is a necessary but not sufficient condition of oxidative stress (15,19). In addition, it is helpful to provide evidence not just of oxidative stress but also of downstream oxidative damage to related physiology, such as neuronal calcium homeostasis or excitability (32)(33)(34)48). To this end, 5xFAD mice were examined using MEMRI, the imaging modality of choice for measuring neuronal LTCC function in vivo (37,(49)(50)(51)73), and by electrophysiology (35,36).…”

“…UBE3A-knockout mice are a model of AS, a genetic neurodevelopmental disorder characterized by hippocampus oxidative stress and impaired goal location based on external cues and other endophenotypes consistent with that in patients with AS (2,31). Because oxidative stress impairs L-type calcium channel (LTCC) function and afterhyperpolarization (AHP; due to reduced calcium entry) (32)(33)(34)(35)(36), we also examined 5xFAD mice for downstream functional oxidative damage produced by excessive free radical production. LTCC function was measured in vivo along the dorsalventral CA1 axis using manganese-enhanced MRI (MEMRI) (37); calcium-dependent AHP in the dorsal hippocampus CA1 subfield was also evaluated (35,36).…”

Dementia-related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits Aβ42 toxicity in Drosophila

“…Other studies have reported that A-induced neuronal hyperexcitability underlying AD epileptic phenotype (170) was a result of Ainduced depolarization of both the neuronal resting membrane potential (E m ) and GABAmediated current reversal potential (E GABA ), leading to aberrant network activity (86). It has also been reported that acute application of A to hippocampal slices causes a hyperpolarization of AP threshold and a reduction in after-hyperpolarization, leading to increased excitability (211).…”