Periodic Reporting for period 3 - Dyn-Syn-Mem (Dynamic mechanisms and functional roles of synaptic plasticity in memory)
Periodo di rendicontazione: 2022-02-01 al 2023-07-31
Activity-dependent plasticity of synaptic transmission together with refinement of neural circuits connectivity are amongst the core mechanisms underlying learning and memory. While there is already extensive knowledge on some of the mechanisms of synaptic plasticity, fundamental questions remain on the dynamics of the underlying molecular events and the functional roles of various forms of synaptic plasticity in information processing, learning and behavior.
Gaining a better knowledge of the molecular and cellular mechanisms of synaptic plasticity will ultimately help design new and better therapeutic candidates for the wide variety of brain diseases that involve synapse dysfunction such as neurodegenerative diseases (e.g. Alzheimer’s disease, Huntington’s disease) or neurodevelopmental diseases (autism spectrum disorders, some forms of mental retardation, etc..)
We previously uncovered basic features of glutamate receptor movements and their role in excitatory synaptic transmission. Our new ground-breaking objectives are: 1) to uncover, in a physiological context, the dynamic mechanisms through which synapses modulate their strength in response to neuronal activity by integrating on different space and time scales the properties of receptor traffic pathways and associated stabilization mechanisms, 2) to use our knowledge and innovative tools to interfere with these trafficking mechanisms in order to decipher the specific roles of different forms of synaptic plasticity in given brain functions and behavioral tasks. For this aim, I lead a team of neurobiologists, physicists and chemists with a collaborative record of accomplishment. We will combine imaging, cellular neurobiology, physiology and behavior to probe the mechanisms and roles of different forms of synaptic plasticity.
New in tissue high-resolution imaging combined with innovative molecular reporters and electrophysiology will allow analysis of receptor traffic during short and long-term synaptic plasticity in physiological conditions. We will probe the interplay between activity-dependent changes in synaptic strength and circuit function with new photo-activable modifiers of receptor traffic with an unprecedented time and space resolution. Use of these tools in vivo will allow identifying the roles of synaptic plasticity in sensory information processing and the various phases of spatial memory formation.
Our aims are to :
Develop new in depth high-resolution imaging, chemical tools and bioprobes that will be of general use in biological sciences. We will make our instruments available to the community through our imaging core facility.
Gain fundamental knowledge on the basic properties and functional roles of AMPAR traffic and stabilization in intact tissue during activity dependent synaptic plasticity.
Develop new molecular tools to modify receptor traffic with light and use these to decipher the link between AMPAR traffic, synaptic plasticity and learning and memory.
Gaining a better knowledge of the molecular and cellular mechanisms of synaptic plasticity will ultimately help design new and better therapeutic candidates for the wide variety of brain diseases that involve synapse dysfunction such as neurodegenerative diseases (e.g. Alzheimer’s disease, Huntington’s disease) or neurodevelopmental diseases (autism spectrum disorders, some forms of mental retardation, etc..)
We previously uncovered basic features of glutamate receptor movements and their role in excitatory synaptic transmission. Our new ground-breaking objectives are: 1) to uncover, in a physiological context, the dynamic mechanisms through which synapses modulate their strength in response to neuronal activity by integrating on different space and time scales the properties of receptor traffic pathways and associated stabilization mechanisms, 2) to use our knowledge and innovative tools to interfere with these trafficking mechanisms in order to decipher the specific roles of different forms of synaptic plasticity in given brain functions and behavioral tasks. For this aim, I lead a team of neurobiologists, physicists and chemists with a collaborative record of accomplishment. We will combine imaging, cellular neurobiology, physiology and behavior to probe the mechanisms and roles of different forms of synaptic plasticity.
New in tissue high-resolution imaging combined with innovative molecular reporters and electrophysiology will allow analysis of receptor traffic during short and long-term synaptic plasticity in physiological conditions. We will probe the interplay between activity-dependent changes in synaptic strength and circuit function with new photo-activable modifiers of receptor traffic with an unprecedented time and space resolution. Use of these tools in vivo will allow identifying the roles of synaptic plasticity in sensory information processing and the various phases of spatial memory formation.
Our aims are to :
Develop new in depth high-resolution imaging, chemical tools and bioprobes that will be of general use in biological sciences. We will make our instruments available to the community through our imaging core facility.
Gain fundamental knowledge on the basic properties and functional roles of AMPAR traffic and stabilization in intact tissue during activity dependent synaptic plasticity.
Develop new molecular tools to modify receptor traffic with light and use these to decipher the link between AMPAR traffic, synaptic plasticity and learning and memory.
During this first period, according to our plan, we have put an extensive effort to develop methods to image and control receptor trafficking. We have made major progress in developing new methods to label and image ENDOGENOUS AMPAR receptor trafficking in intact brain tissue. This includes new ligands for scaffold proteins as well as a new animal model and imaging modality.
Using these tools, we have started to study various neurophysiological aspects such as the role of AMPAR diffusion in short term plasticity, the mechanism of PSD component destabilization in Long Term depression and the role of AMPAR traffic in LTP and learning. Regarding the latter, amajor progress was achieved in studying the role of AMPAR surface trafficking on in vivo LTP by demonstrating that AMPAR-dependent synaptic plasticity initiates cortical remapping and adaptive behaviors during sensory experience
Using these tools, we have started to study various neurophysiological aspects such as the role of AMPAR diffusion in short term plasticity, the mechanism of PSD component destabilization in Long Term depression and the role of AMPAR traffic in LTP and learning. Regarding the latter, amajor progress was achieved in studying the role of AMPAR surface trafficking on in vivo LTP by demonstrating that AMPAR-dependent synaptic plasticity initiates cortical remapping and adaptive behaviors during sensory experience
We have advanced the field of cellular imaging and neuroscience significantly beyond the state of the art. For example, our work provides new ligands for receptors and scaffold proteins important for synaptic transmission that we allow us to gain better insight and manipulate synaptic transmission. Scientifically the most unexpected finding so far is that of the role of AMPAR trafficking in vivo, as we show that AMPAR trafficking mediates synaptic potentiation in vivo in mice with intact whiskers, that whisker trimming rapidly saturates spared-whisker responses, that synaptic potentiation causes the enhancement of spared-whisker-evoked response and that synaptic potentiation facilitates the behavioral recovery during cortical remapping.
For the remaining of the project, we will exploit the tools developed up to now, to investigate key aspects of the plasticity of synaptic transmission in behaviorally relevant paradigms.
For the remaining of the project, we will exploit the tools developed up to now, to investigate key aspects of the plasticity of synaptic transmission in behaviorally relevant paradigms.