Periodic Reporting for period 4 - Dyn-Syn-Mem (Dynamic mechanisms and functional roles of synaptic plasticity in memory)
Période du rapport: 2023-08-01 au 2025-02-28
Communication between brain cells at synapses—the points of contact where information is exchanged—is a fundamental process enabling the brain to learn, remember, and adapt. Traditionally, scientists believed that short-term changes in synaptic strength, which allow neural circuits to rapidly adapt, were mainly determined by variations in the amount of chemical messengers (neurotransmitters) released by the sending neuron. However, accumulating evidence suggests that the receiving side of the synapse, and especially the behavior of AMPA-type glutamate receptors (AMPARs), also plays a critical role in these fast adjustments. The main goal of our project has been to unravel how both presynaptic (sending side) and postsynaptic (receiving side) mechanisms, including the mobility and function of AMPARs, work together to shape the flexibility and efficiency of synaptic communication. Our broader ambition is to connect molecular events at individual synapses with the larger-scale functioning of brain circuits involved in learning, memory, and adaptive behavior. In this final period, we conclude that short-term synaptic adaptation is orchestrated by a precise balance between neurotransmitter release and the dynamic regulation of AMPAR mobility and responsiveness, and that this synergy is crucial for effective information processing in the brain.
From the project’s outset, we have developed and applied advanced molecular, imaging, and genetic tools to visualize, manipulate, and track AMPARs and associated proteins in brain tissue. This has involved the close collaboration of neurobiologists, chemists, and computer scientists. In the first phase, we established new high-resolution imaging techniques and biosensors, as well as novel mouse models that allow us to control receptor movement in brain slices and in living animals. We performed the first multicolor superresolution visualization of AMPA, NMDA, and mGluR receptors at synapses, offering an unprecedented look at their nanoscale organization.
As the project progressed, we refined these tools and began to exploit them to answer core questions in synaptic biology. We published key discoveries in leading journals, including the demonstration that AMPARs are mobile in intact brain tissue and that blocking their movement prevents both long-term potentiation (LTP)—a cellular basis for memory—and long-term memory formation itself. We also showed that the mobility of AMPARs regulates short-term synaptic plasticity, providing evidence that both rapid and long-lasting changes at synapses depend on the dynamic behavior of these receptors. Additional achievements include the development of new biosensors to monitor and label endogenous proteins in live neurons, and pioneering studies on synaptic cleft adhesion proteins.
Most recently, we have used these tools to dissect the precise contributions of presynaptic and postsynaptic mechanisms in rapid, activity-dependent synaptic adaptation. We found that different synapses rely on distinct strategies: some emphasize AMPAR desensitization, others on the trapping and release of AMPARs, to fine-tune responses to high-frequency neural activity. Furthermore, we discovered that signaling pathways activated during long-term synaptic changes (such as those involving CaMKII) can rapidly regulate AMPAR mobility, acting as a gain control for short-term synaptic responses and influencing how signals are integrated and transmitted within neural networks. These results have been shared widely through publications and presentations, and our new tools are now being used by other researchers to investigate synaptic function in various brain regions and disease models.
As the project progressed, we refined these tools and began to exploit them to answer core questions in synaptic biology. We published key discoveries in leading journals, including the demonstration that AMPARs are mobile in intact brain tissue and that blocking their movement prevents both long-term potentiation (LTP)—a cellular basis for memory—and long-term memory formation itself. We also showed that the mobility of AMPARs regulates short-term synaptic plasticity, providing evidence that both rapid and long-lasting changes at synapses depend on the dynamic behavior of these receptors. Additional achievements include the development of new biosensors to monitor and label endogenous proteins in live neurons, and pioneering studies on synaptic cleft adhesion proteins.
Most recently, we have used these tools to dissect the precise contributions of presynaptic and postsynaptic mechanisms in rapid, activity-dependent synaptic adaptation. We found that different synapses rely on distinct strategies: some emphasize AMPAR desensitization, others on the trapping and release of AMPARs, to fine-tune responses to high-frequency neural activity. Furthermore, we discovered that signaling pathways activated during long-term synaptic changes (such as those involving CaMKII) can rapidly regulate AMPAR mobility, acting as a gain control for short-term synaptic responses and influencing how signals are integrated and transmitted within neural networks. These results have been shared widely through publications and presentations, and our new tools are now being used by other researchers to investigate synaptic function in various brain regions and disease models.
Our project has moved the field beyond previous models by showing that postsynaptic receptor mobility is as important as presynaptic neurotransmitter release for fast synaptic plasticity. We have developed and validated new mouse models and imaging methods that are now becoming reference tools for the neuroscience community. By revealing that the nanoscale organization and mobility of AMPARs directly govern both rapid and lasting changes in synaptic strength, we have opened up new avenues for understanding how the brain adapts and encodes information.
Looking forward, the tools and insights developed here are expected to drive further discoveries in brain science, especially concerning the molecular basis of learning and memory, and the pathological mechanisms underlying neurological disorders where synaptic function is impaired. We anticipate that our molecular strategies to manipulate receptor mobility will be adapted to probe the roles of other synaptic proteins, broadening their impact. Moreover, these advances lay the groundwork for novel therapeutic approaches aimed at restoring normal synaptic plasticity in diseases such as Alzheimer’s, Huntington’s, and other disorders involving disrupted communication between neurons.
Looking forward, the tools and insights developed here are expected to drive further discoveries in brain science, especially concerning the molecular basis of learning and memory, and the pathological mechanisms underlying neurological disorders where synaptic function is impaired. We anticipate that our molecular strategies to manipulate receptor mobility will be adapted to probe the roles of other synaptic proteins, broadening their impact. Moreover, these advances lay the groundwork for novel therapeutic approaches aimed at restoring normal synaptic plasticity in diseases such as Alzheimer’s, Huntington’s, and other disorders involving disrupted communication between neurons.