Excitability and Synaptic Alterations in the Cerebellum of APP/PS1 Mice
Open Access
- 12 April 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (4), e34726
- https://doi.org/10.1371/journal.pone.0034726
Abstract
In Alzheimer's disease (AD), the severity of cognitive symptoms is better correlated with the levels of soluble amyloid-beta (Aβ) rather than with the deposition of fibrillar Aβ in amyloid plaques. In APP/PS1 mice, a murine model of AD, at 8 months of age the cerebellum is devoid of fibrillar Aβ, but dosage of soluble Aβ1–42, the form which is more prone to aggregation, showed higher levels in this structure than in the forebrain. Aim of this study was to investigate the alterations of intrinsic membrane properties and of synaptic inputs in Purkinje cells (PCs) of the cerebellum, where only soluble Aβ is present. PCs were recorded by whole-cell patch-clamp in cerebellar slices from wild-type and APP/PS1 mice. In APP/PS1 PCs, evoked action potential discharge showed enhanced frequency adaptation and larger afterhyperpolarizations, indicating a reduction of the intrinsic membrane excitability. In the miniature GABAergic postsynaptic currents, the largest events were absent in APP/PS1 mice and the interspike intervals distribution was shifted to the left, but the mean amplitude and frequency were normal. The ryanodine-sensitive multivescicular release was not altered and the postsynaptic responsiveness to a GABAA agonist was intact. Climbing fiber postsynaptic currents were normal but their short-term plasticity was reduced in a time window of 100–800 ms. Parallel fiber postsynaptic currents and their short-term plasticity were normal. These results indicate that, in the cerebellar cortex, chronically elevated levels of soluble Aβ1–42 are associated with alterations of the intrinsic excitability of PCs and with alterations of the release of GABA from interneurons and of glutamate from climbing fibers, while the release of glutamate from parallel fibers and all postsynaptic mechanisms are preserved. Thus, soluble Aβ1–42 causes, in PCs, multiple functional alterations, including an impairment of intrinsic membrane properties and synapse-specific deficits, with differential consequences even in different subtypes of glutamatergic synapses.This publication has 44 references indexed in Scilit:
- Probing the Biology of Alzheimer's Disease in MiceNeuron, 2010
- Stereological evaluation of the volume and volume fraction of intracranial structures in magnetic resonance images of patients with Alzheimer's diseaseAnnals of Anatomy - Anatomischer Anzeiger, 2009
- Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptideNature Reviews Molecular Cell Biology, 2007
- Aβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathologyEMBO Reports, 2006
- The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to TherapeuticsScience, 2002
- Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivoNature, 2002
- Soluble pool of A? amyloid as a determinant of severity of neurodegeneration in Alzheimer's diseaseAnnals of Neurology, 1999
- Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's DiseaseThe American Journal of Pathology, 1999
- Correlations of synaptic and pathological markers with cognition of the elderlyNeurobiology of Aging, 1995
- Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairmentAnnals of Neurology, 1991