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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.

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.

Synaptic transmission was studied in hippocampal slices from aged (12–14 months of age) TAS10 mice overexpressing the human form of the amyloid precursor protein harboring the Swedish mutation. A significant deficit in the input-output relationship of glutamatergic synapses in the CA3–CA1 Schaffer collateral pathway was observed, while synaptic transmission in the medial perforant pathway of the dentate gyrus was comparatively preserved. Despite this deficit, relative levels of short- and long-term synaptic plasticity in the CA1 region were similar to those observed in wildtype slices. Specifically, paired pulse facilitation, frequency facilitation (at frequencies of 1, 5, and 10 Hz), and long-term potentiation induced by a theta burst stimulation paradigm were all normal in the CA3–CA1 synapses of TAS10 hippocampal slices. However, synchronized network activity induced by bath application of 4-aminopyridine (4-AP) was compromised. Thus, the frequency of synchronous events induced by 100 μM 4-AP was significantly lower in TAS10 hippocampal slices (inter-event interval: WT, 2.4 ± 0.6 s; TAS10, 6.9 ± 1.7 s). To study γ-aminobutyric acid (GABA)ergic synaptic transmission NBQX (20 μM) and D-AP5 (50 μM) were added in order to isolate bicuculline-sensitive GABA-mediated synchronous network activity. The GABAergic network activity was not significantly different from wildtype in terms of frequency. This study suggests that the deficit in glutamatergic synaptic transmission observed in the TAS10 hippocampal slices, may be coupled with alterations in synchronous network activity, which in turn would lead to deficient information processing. © 2004 Wiley-Liss, Inc.