At the onset of Alzheimer's disease (AD), accumulation of oligomeric amyloid-β (Aβ) correlates with local hyperexcitability, possibly due to dyshomeostasis of extracellular glutamate. However, the interplay between Aβ oligomers and extracellular glutamate accumulation remains unresolved. We use an in silico approach to characterize the putative underpinnings of Aβ-dependent modulations of extracellular glutamate. We first consider how Aβ modifies the expression of astrocytic glutamate transporters (GLT1) and how it impacts extracellular glutamate time course. Accordingly, we develop a mathematical model for glutamate diffusion and uptake at synaptic terminals and their surroundings. Our model predicts that above a threshold Aβ concentration, astrocytic GLT1 transporters cannot prevent the accumulation of extracellular glutamate. This, in turn, promotes a positive feedback on synaptic glutamate release that favors excitotoxicity and neuronal hyperactivity. Next, we complement our model including calcium-dependent Aβ production and glutamate release. The interaction of multiple positive feedback loops of signaling can account for different tissue states, overcoming the traditional dichotomy of healthy and excitotoxic conditions. Specifically, changes in the basal firing activity can promote intermediate conditions useful to either predict AD's degeneration or offer new therapeutic perspectives. Our results support the notion of AD as a multistage pathology where transitions can follow multiple pathways, such as Aβ accumulation, excitotoxicity, or calcium dysregulation.

Aβ-dependent alteration of astrocytic GLT1 expression can trigger the multistage progression of Alzheimer's disease

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PS-2-B -  Neural Excitability, Synapses, and Glia: Cellular Mechanisms

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Colleagues and Friends:

I am very happy to welcome you to the 14th annual Canadian Neuroscience Meeting, and to the first virtual edition of our meeting. I want to highlight the important work the CAN meeting chair, **Roger Thompson** and co-chair, **Alyson Fournier**, did to put together the great program we are offering this year. Moving to a virtual format required a complete re-design of the program, and both Roger and Alyson did a splendid job in providing us with an appealing and well adapted program for our first virtual event. I wish to thank them for this very important effort.

Highlights of this year’s scientific meeting include invited speakers **Michael Hausser, Franck Polleux, Gwyneth Card, Magdalena Götz**and Brain Prize winner **Huda Zoghbi**. Plenary and parallel symposia, proposed by our members complete our diverse [scientific program.](https://can-acn.org/meeting-2021/program-2021/)

The 2021 Advocacy session, chaired and organized by CAN advocacy committee chair **Karun Singh**, will feature a special lecture and question period with Member of Parliament and past Science Minister **Kirsty Duncan**. This will be followed by a short overview of CAN’s advocacy activities over the last year. We invite you to participate in this session for insight from Dr. Duncan on the workings of Parliament Hill, and to learn more about what CAN has been doing to promote neuroscience research in Canada.

We are also excited to host **Lisa Willis** in the Equity Diversity and Inclusion session, organized by EDI committee chair **Jibran Khokhar**.

A special highlight of our meeting will be the lectures by award-winning young neuroscientists. We are please to host the CAN 2020 Young Investigator Award winner **Mihaela Iordanova**, and CAN 2021 Young Investigator Award winners **Aaron Phillips** and **Tabrez Siddiqui**. Highlights will also include presentation by the top three winners of the CAN-CIHR-INMHA Brain Star Award winners, **Claire Gizowski, Nuria Daviu Abant** and **Lukas Tamayo-Orrego**.

Independently organized satellite symposia complement and complete this exciting program, check them out here: https://can-acn.org/meeting-2021/2021-satellite-symposia/

Some of the most engaging sessions are always the poster sessions featuring the work of our trainees, so make sure to log in to Gather Town during the poster sessions to chat with the presenters.
We hope you enjoy this program, and look forward to welcoming you, virtually.

Shernaz Bamji

President of the Canadian Association for Neuroscience

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Giulio Bonifazi

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Aβ-dependent alteration of astrocytic GLT1 expression can trigger the multistage progression of Alzheimer's disease

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