Astrocytic signaling upon Aβ-mediated excitotoxicity
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1
Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Portugal
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2
Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Portugal
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3
Center for Chronic Disease Studies (CEDOC), Portugal
Alzheimer’s Disease (AD) is an aged-dependent neurodegenerative disease characterized by progressive deterioration of cognitive function. Amyloid beta (Aβ) accumulation is considered the principal hallmark of AD, being associated with the disruption of synaptic transmission and plasticity, such as, long-term potentiation (LTP) (Ferrer I. et al., 2012). Astrocytes are able to modulate synaptic plasticity, since Ca2+-dependent release of gliotransmitters, such as glutamate, ATP, and D-serine, plays a critical role in hippocampal LTP induction (Pascual, O. et al., 2005). Aβ deposition is able to disrupt Ca2+-signaling in astrocytes (Angelova PR. et al., 2014), which can lead to the abnormal Ca2+-dependent release of gliotransmitters. In turn, this anomalous Ca2+-dependent release of gliotransmitters can contribute to the increase in neuronal excitability that leads to the disruption of synaptic transmission and plasticity.
Thus, knowing that Ca2+-dependent release of gliotransmitters can occur in a SNARE-dependent manner, the aim of the present work was to investigate the role of SNARE-dependent gliotransmitters release from astrocytes under Aβ-mediated excitotoxicity upon synaptic transmission and plasticity.
fEPSP were recorded from CA1 area of hippocampal slices from WT and dn-SNARE mice, in which the SNARE-dependent release of gliotransmitters is selectively impaired in astrocytes. Importantly, the SNARE domain expression can be suppressed by doxycycline (Dox, 25 µl/mL) administration. Hippocampal slices were pre-treated with Aβ1-42 oligomers (200 nM) for 3h. LTP was induced by θ-burst stimulation in the Schaffer collaterals/CA1 area.
The θ-burst stimulation increased fEPSP slope by 38±7,1% (n=2) in WT (Dox +) mice and by 31±8,9% (n=2) in dn-SNARE (Dox +), while in the presence of Aβ1-42 oligomers (200 nM), the same induction paradigm, lead to the disruption of LTP on both WT (Dox +) and dn-SNARE (Dox +). In dn-SNARE (-Dox) mice, the LTP magnitude was 35±7,4% in the absence of Aβ1-42 oligomers (200 nM) and 31±3,8% in its presence (p>0.05, n=5).
These results suggest that astrocytes play an active role in Aβ-mediated effects in synaptic transmission and plasticity, mainly by the Ca2+-dependent release of gliotransmitters, since in dn-SNARE (-Dox), where the SNARE-dependent release of gliotransmitters is selective compromised, we observed a recovery of LTP in the presence of Aβ oligomers.
Acknowledgements
This project was funded by Fundação para a Ciência e a Tecnologia (PTDC/BTM-SAL/32147/2017) and by Santa Casa da Misericórdia (MB-37-2017).
References
Ferrer, I. Defining Alzheimer as a common age-related neurodegenerative process not inevitably leading to dementia. Prog. Neurobiol. 97, 38–51 (2012).
Pascual, O. et al. Astrocytic Purinergic Signaling Coordinates Synaptic Networks. Science. 310, 113–116 (2005).
Angelova, P. R. & Abramov, A. Y. Interaction of neurons and astrocytes underlies the mechanism of Aβ-induced neurotoxicity. Biochem. Soc. Trans. 42, 1286–1290 (2014).
Keywords:
Astrocytes,
gliotransmission,
synaptic plasticity,
amyloid-beta (Aβ),
Neurotoxicity
Conference:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019.
Presentation Type:
Poster presentation
Topic:
Glia / Neuroinflammation
Citation:
Gomes
JI,
Gomes
JF,
Miranda
HV,
Sebastião
AM,
Diógenes
M and
Vaz
SH
(2019). Astrocytic signaling upon Aβ-mediated excitotoxicity.
Front. Cell. Neurosci.
Conference Abstract:
XVI Meeting of the Portuguese Society for Neuroscience (SPN2019).
doi: 10.3389/conf.fncel.2019.01.00023
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Received:
16 Apr 2019;
Published Online:
27 Sep 2019.
*
Correspondence:
Dr. Sandra H Vaz, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal, svaz@medicina.ulisboa.pt