Dataset Information

TRPA1 channels promote astrocytic Ca²⁺ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-? peptide.

ABSTRACT:

Background

Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease (AD). However, the key mechanisms that maintain plasticity of synapses during adulthood or initiate synapse dysfunction in AD remain unknown. Recent studies suggest that astrocytes contribute to functional changes observed during synaptic plasticity and play a major role in synaptic dysfunction but astrocytes behavior and involvement in early phases of AD remained largely undefined.

Methods

We measure astrocytic calcium activity in mouse CA1 hippocampus stratum radiatum in both the global astrocytic population and at a single cell level, focusing in the highly compartmentalized astrocytic arbor. Concurrently, we measure excitatory post-synaptic currents in nearby pyramidal neurons.

Results

We find that application of soluble A? oligomers (A?o) induced fast and widespread calcium hyperactivity in the astrocytic population and in the microdomains of the astrocyte arbor. We show that astrocyte hyperactivity is independent of neuronal activity and is repaired by transient receptor potential A1 (TRPA1) channels blockade. In return, this TRPA1 channels-dependent hyperactivity influences neighboring CA1 neurons triggering an increase in glutamatergic spontaneous activity. Interestingly, in an AD mouse model (APP/PS1-21 mouse), astrocyte calcium hyperactivity equally takes place at the beginning of A? production, depends on TRPA1 channels and is linked to CA1 neurons hyperactivity.

Conclusions

Our experiments demonstrate that astrocytes contribute to early A?o toxicity exhibiting a global and local Ca²⁺ hyperactivity that involves TRPA1 channels and is related to neuronal hyperactivity. Together, our data suggest that astrocyte is a frontline target of A?o and highlight a novel mechanism for the understanding of early synaptic dysregulation induced by soluble A?o species.

SUBMITTER: Bosson A

PROVIDER: S-EPMC5501536 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TRPA1 channels promote astrocytic Ca<sup>2+</sup> hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide.

Bosson Anthony A Paumier Adrien A Boisseau Sylvie S Jacquier-Sarlin Muriel M Buisson Alain A Albrieux Mireille M

Molecular neurodegeneration 20170706 1

<h4>Background</h4>Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease (AD). However, the key mechanisms that maintain plasticity of synapses during adulthood or initiate synapse dysfunction in AD remain unknown. Recent studies suggest that astrocytes contribute to functional changes observed during synaptic plasticity and play a major role in synaptic dysfunction but astrocytes behavior and involvement in early phases of AD remained largely undefined.<h4>M ...[more]

PMID: 28683776

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Project description:Epilepsy is a group of neurological disorders commonly associated with the neuronal malfunction leading to generation of seizures. Recent reports point to a possible contribution of astrocytes into this pathology. We used the lithium-pilocarpine model of status epilepticus (SE) in rats to monitor changes in astrocytes. Experiments were performed in acute hippocampal slices 2-4 weeks after SE induction. Nissl staining revealed significant neurodegeneration in the pyramidal cell layers of hippocampal CA1, CA3 areas, and the hilus, but not in the granular cell layer of the dentate gyrus. A significant increase in the density of astrocytes stained with an astrocyte-specific marker, sulforhodamine 101, was observed in CA1 stratum (str.) radiatum. Astrocytes in this area were also whole-cell loaded with a morphological tracer, Alexa Fluor 594, for two-photon excitation imaging. Sholl analyses showed no changes in the size of the astrocytic domain or in the number of primary astrocytic branches, but a significant reduction in the number of distal branches that are resolved with diffraction-limited light microscopy (and are thought to contain Ca2+ stores, such as mitochondria and endoplasmic reticulum). The atrophy of astrocytic branches correlated with the reduced size, but not overall frequency of Ca2+ events. The volume tissue fraction of nanoscopic (beyond the diffraction limit) astrocytic leaflets showed no difference between control and SE animals. The results of spatial entropy-complexity spectrum analysis were also consistent with changes in ratio of astrocytic branches vs. leaflets. In addition, we observed uncoupling of astrocytes through the gap-junctions, which was suggested as a mechanism for reduced K+ buffering. However, no significant difference in time-course of synaptically induced K+ currents in patch-clamped astrocytes argued against possible alterations in K+ clearance by astrocytes. The magnitude of long-term-potentiation (LTP) was reduced after SE. Exogenous D-serine, a co-agonist of NMDA receptors, has rescued the initial phase of LTP. This suggests that the reduced Ca2+-dependent release of D-serine by astrocytes impairs initiation of synaptic plasticity. However, it does not explain the failure of LTP maintenance which may be responsible for cognitive decline associated with epilepsy.

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Dataset Information

TRPA1 channels promote astrocytic Ca²⁺ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-? peptide.

Background

Methods

Results

Conclusions

Publications

TRPA1 channels promote astrocytic Ca<sup>2+</sup> hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-? peptide.

Background

Methods

Results

Conclusions

Publications

TRPA1 channels promote astrocytic Ca<sup>2+</sup> hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

TRPA1 channels promote astrocytic Ca²⁺ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-? peptide.