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

Abstract

BackgroundExcessive 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.MethodsWe 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.ResultsWe find that application of soluble Aβ oligomers (Aβo) 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 Aβ production, depends on TRPA1 channels and is linked to CA1 neurons hyperactivity.ConclusionsOur experiments demonstrate that astrocytes contribute to early Aβo 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 Aβo and highlight a novel mechanism for the understanding of early synaptic dysregulation induced by soluble Aβo species.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0194-8) contains supplementary material, which is available to authorized users.

Inability to Smell Peppermint Is Related to Cognitive Decline: A Prospective Community-Based Study

“…Other components include menthofuran, 1,8-cineol, terpenoids, and flavonoids such as eriocitrin, hesperidin, and kaempferol 7-O-rutinoside [35]. The main cellular receptor for peppermint odor is transient receptor potential cation channel subfamily A member 1, which is associated with AD [36,37]. Peppermint (Mentha piperita) essential oil, which has high levels of menthol/menthone and characteristic in vitro cholinergic inhibitory, calcium regulatory, and GABAA/nicotinic receptor-binding properties, beneficially modulated performance on demanding cognitive tasks and attenuated the increase in mental fatigue associated with extended cognitive task performance in healthy adults [38].…”

Investigation of Cuprizone-Induced Demyelination in mGFAP-Driven Conditional Transient Receptor Potential Ankyrin 1 (TRPA1) Receptor Knockout Mice

“…Since TRPA1 can be triggered by several noxious stimuli, including inflammation, tissue damage or oxidative stress on one hand, and astrocytes influence the extent of this toxin-induced demyelination on the other [29], we assumed that this receptor might modulate the demyelination process. Numerous earlier studies have provided substantial morphological and functional evidence that astrocytes express the TRPA1 receptor, functioning as a regulator of resting Ca 2+ levels [8,9,24,30,31]. In a very recent study, Oh et al, using the cell-type-specific gene-silencing and ultrasensitive sniffer-patch techniques, identified astrocytes as the cellular target and TRPA1 as the molecular sensor for the low intensity, low frequency ultrasound (LILFU).…”

TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases

“…TRPA1 was first identified in mouse hippocampal astrocytes and associated with Aβ-mediated Ca 2+ signaling (Figure 2F; Lee et al, 2016). The cause of Aβ oligomer-mediated fast Ca 2+ signaling appears to be the hyperactivation of TRPA1 (Bosson et al, 2017). TRPA1induced Ca 2+ signaling initiates the release of inflammatory factors such as PP2B, NF-κB, and NFAT (Figure 2F).…”

“…Until now, the role of TRPA1 in neurons has only been reported on with respect to pain and inflammation, although recent studies have revealed a potential involvement in AD pathogenesis. Deposition of Aβ is an important factor in the exacerbation of AD, and soluble Aβ oligomers mediate fast and widespread Ca 2+ influx in astrocytes (Bosson et al, 2017). TRPA1 was first identified in mouse hippocampal astrocytes and associated with Aβ-mediated Ca 2+ signaling (Figure 2F; Lee et al, 2016).…”