Final Report Summary - ADOS (AMPA Receptor Dynamic Organization and Synaptic transmission in health and disease)
The main aim of our project was to progress our understanding of the mechanism of synaptic plasticity, which most likely underlies learning and memory. We wanted to understand both the basic mechanism of synaptic plasticity of excitatory glutamatergic synapses, and also contribute to our understanding of the defects in synaptic function in neurodegenerative diseases such as Alzheimer and Huntington’s disease.
We had chosen to concentrate on the analysis of AMPA receptor trafficking, as 1) AMPA receptors represent the main glutamate receptors responsible for excitatory neurotransmission in the brain, 2) AMPA receptor trafficking is thought to be the main mechanism to control the efficacy of synaptic transmission. Hence, within the framework that to change synaptic efficacy during learning, the number of AMPA receptors have to be regulated, we set to devise a number of new methodological approaches to both measure and control AMPA receptor trafficking pathways. We concentrated on three trafficking pathways. AMPA receptor surface diffusion in the plane of the membrane (a pathway that the PI of this grant identified in 2002), AMPA receptor intracellular transport (a pathway that had resisted investigation up to very recently), AMPA receptor recycling between intracellular compartment and the cell surface (the key pathways to control AMPA receptor availability at the cell surface).
For each of these pathways, we developed specific new imaging methods that have been disseminated through publications and our core facility the Bordeaux imaging Center, part of the national infrastructure France bioImaging and part of the European infrastructure EuroBioImaging. We developed new small ligands for super resolution imaging, new analysis software that accelerated by a factor of thousand the speed of image analysis. We developed a new platform for high throughput super resolution imaging. We developed a new method to image AMPA receptor intracellular transport. We developed a new pipeline based on directed evolution to identify new highly specific ligands for scaffold proteins. We developed a new method to control AMPA receptor surface diffusion in live neurons, brain slices and in vivo. This method has a very promising future to allow the analysis of the contribution of synaptic plasticity in various learning paradigms.
The main results obtained in the course of this grant are :
- The demonstration that the initial phase of synaptic potentiation in response to high-frequency stimulation is totally dependent on AMPA receptor diffusion trapping. Because this process of synaptic potentiation is thought to be a major player in the process of learning and memory, the identification of the key role of AMPA receptor diffusion trapping opens a new door to understand the link between synaptic plasticity and learning.
- The demonstration that AMPA receptor intracellular transport and AMPA receptor recycling are highly regulated by neuronal activity. These findings highlight the variety of mechanism that the neurons use to regulate AMPA receptor number at synapses.
- The demonstration that AMPA receptor surface diffusion is considerably altered in two models of neurodegenerative disease (Huntington and Alzheimer’s disease). These results propose a new molecular explanation for the early cognitive deficits observed in these diseases and may provide new targets for drugs aiming at these devastating pathologies.
In conclusion, through this ERC grant, we have made important progress in our understanding of excitatory synaptic function and developed a series of new imaging and analytical tools. We have obtained a series of results that open several new doors to our understanding of the cellular substrates of learning and memory. Exploitation of these tools and exploration of this fascinating link between synaptic plasticity and learning is the topic of the new ERC grant Dyn-Syn-Mem granted to the PI and starting in 2019.
We had chosen to concentrate on the analysis of AMPA receptor trafficking, as 1) AMPA receptors represent the main glutamate receptors responsible for excitatory neurotransmission in the brain, 2) AMPA receptor trafficking is thought to be the main mechanism to control the efficacy of synaptic transmission. Hence, within the framework that to change synaptic efficacy during learning, the number of AMPA receptors have to be regulated, we set to devise a number of new methodological approaches to both measure and control AMPA receptor trafficking pathways. We concentrated on three trafficking pathways. AMPA receptor surface diffusion in the plane of the membrane (a pathway that the PI of this grant identified in 2002), AMPA receptor intracellular transport (a pathway that had resisted investigation up to very recently), AMPA receptor recycling between intracellular compartment and the cell surface (the key pathways to control AMPA receptor availability at the cell surface).
For each of these pathways, we developed specific new imaging methods that have been disseminated through publications and our core facility the Bordeaux imaging Center, part of the national infrastructure France bioImaging and part of the European infrastructure EuroBioImaging. We developed new small ligands for super resolution imaging, new analysis software that accelerated by a factor of thousand the speed of image analysis. We developed a new platform for high throughput super resolution imaging. We developed a new method to image AMPA receptor intracellular transport. We developed a new pipeline based on directed evolution to identify new highly specific ligands for scaffold proteins. We developed a new method to control AMPA receptor surface diffusion in live neurons, brain slices and in vivo. This method has a very promising future to allow the analysis of the contribution of synaptic plasticity in various learning paradigms.
The main results obtained in the course of this grant are :
- The demonstration that the initial phase of synaptic potentiation in response to high-frequency stimulation is totally dependent on AMPA receptor diffusion trapping. Because this process of synaptic potentiation is thought to be a major player in the process of learning and memory, the identification of the key role of AMPA receptor diffusion trapping opens a new door to understand the link between synaptic plasticity and learning.
- The demonstration that AMPA receptor intracellular transport and AMPA receptor recycling are highly regulated by neuronal activity. These findings highlight the variety of mechanism that the neurons use to regulate AMPA receptor number at synapses.
- The demonstration that AMPA receptor surface diffusion is considerably altered in two models of neurodegenerative disease (Huntington and Alzheimer’s disease). These results propose a new molecular explanation for the early cognitive deficits observed in these diseases and may provide new targets for drugs aiming at these devastating pathologies.
In conclusion, through this ERC grant, we have made important progress in our understanding of excitatory synaptic function and developed a series of new imaging and analytical tools. We have obtained a series of results that open several new doors to our understanding of the cellular substrates of learning and memory. Exploitation of these tools and exploration of this fascinating link between synaptic plasticity and learning is the topic of the new ERC grant Dyn-Syn-Mem granted to the PI and starting in 2019.