Abstract
ABSTRACTAccumulation 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.
Highlights
Beta-amyloid peptides (Ab) are widely believed to play an important role in the pathogenesis of Alzheimer’s disease (AD) (Hardy and Higgins, 1992; Pimplikar, 2009)
Central nervous system (CNS) accumulation of soluble Ab occurs early in the disease process and it grows as the pathology becomes more advanced and Ab-rich amyloid plaques appear within the neuronal parenchyma (Jacobsen et al, 2006; Naslund et al, 2000)
The concentration used in this study has been frequently used for in vitro studies of synaptic function and it has been shown to both impair (Lambert et al, 1998; Lauren et al, 2009; Puzzo et al, 2005; Wang et al, 2004) and to facilitate (Li et al, 2009) hippocampal long-term potentiation (LTP)
Summary
Beta-amyloid peptides (Ab) are widely believed to play an important role in the pathogenesis of Alzheimer’s disease (AD) Numerous neurophysiological studies of transgenic mice which overproduce Ab have been performed over the last 15 years, in the attempt to understand how AD-associated Ab pathology disturbs CNS function (Randall et al, 2010). These studies have frequently concentrated on the analysis of synaptic function and plasticity in hippocampus and cerebral cortex (Fitzjohn et al, 2008; Jacobsen et al, 2006; Tamagnini et al, 2012; Witton et al, 2010). The concentration used in this study has been frequently used for in vitro studies of synaptic function and it has been shown to both impair (Lambert et al, 1998; Lauren et al, 2009; Puzzo et al, 2005; Wang et al, 2004) and to facilitate (Li et al, 2009) hippocampal long-term potentiation (LTP)
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