Aberrant Excitatory Neuronal Activity and Compensatory Remodeling of Inhibitory Hippocampal Circuits in Mouse Models of Alzheimer's Disease

Abstract

Neural network dysfunction may play an important role in Alzheimer's disease (AD). Neuronal circuits vulnerable to AD are also affected in human amyloid precursor protein (hAPP) transgenic mice. hAPP mice with high levels of amyloid-beta peptides in the brain develop AD-like abnormalities, including cognitive deficits and depletions of calcium-related proteins in the dentate gyrus, a region critically involved in learning and memory. Here, we report that hAPP mice have spontaneous nonconvulsive seizure activity in cortical and hippocampal networks, which is associated with GABAergic sprouting, enhanced synaptic inhibition, and synaptic plasticity deficits in the dentate gyrus. Many Abeta-induced neuronal alterations could be simulated in nontransgenic mice by excitotoxin challenge and prevented in hAPP mice by blocking overexcitation. Aberrant increases in network excitability and compensatory inhibitory mechanisms in the hippocampus may contribute to Abeta-induced neurological deficits in hAPP mice and, possibly, also in humans with AD.

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

“…Consistent with the effects of hTau‐A152T and hTau‐WT on evoked and spontaneous epileptic activity, expression of either hTau species enhanced the increased risk of early death in hAPP mice, which have epileptiform activity even in the absence of hTau overexpression 46, 49. hTau‐A152T was more detrimental in this regard than hTau‐WT.…”

“…We therefore crossed hTau‐A152T (L1) mice and hTau‐WT (L32) mice with hAPP transgenic mice from line J20 (hAPP‐J20) (Fig 11A–D). hAPP‐J20 mice have pathologically elevated levels of human Aβ in the brain, increased risk of early death (most likely from epileptic activity), and AD‐like features, including memory problems, behavioral alterations, synaptic impairments, amyloid plaques, neuritic dystrophy, astrocytosis, and microgliosis 49, 50, 51, 52, 53.…”

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

“…We next looked for immunohistochemical changes in the hippocampus that are typically caused by epileptic activity 23, 24, 25, 26. Compared with NTG controls, SYN mice had reduced levels of calbindin in granule cells of the dentate gyrus and the stratum radiatum of CA1 (Fig.…”

“…These mice exhibit robust epileptic activity and have dysregulated gamma activity 22, 26. A side‐by‐side comparison of EEG recordings in SYN and hAPP mice matched for age and background strain revealed clear differences in resting spectral power.…”

Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

“…A test stimulus was chosen at approximately 30%e40% of the maximum evoked responses. All slices included in this study presented, under basal stimulation, a single fEPSP not contaminated by multiple, back-propagating, somatic population spikes, which are an index of increased excitability and are related to in vivo epileptic discharges (Arrieta-Cruz et al, 2010;Palop et al, 2007). fEPSP slope or amplitude were routinely measured and expressed as the percentage of the respective 5 minutes averaged value preceding the exposure to OLE and/or suberoylanilide hydroxamic acid (SAHA, Sigma-Aldrich) treatment or LTP induction (baseline).…”