Physiological role of AMPAR nanoscale organization at basal state and during synaptic plasticities

Abstract : The brain is a complex network of interconnected neurons responsible for all our cognitive functions and behaviors. Neurons receive inputs at specialized contact zones named synapses which convert an all or none electrical signal to a chemical one, through the release of neurotransmitters. This chemical signal is then turned back in a tunable electrical signal by receptors to neurotransmitters. However, a single neuron receives thousands of inputs coming from several neurons in a spatial- and temporal-dependent manner. The precise mechanism by which neurons receive, integrate and transmit this synaptic inputs is highly complex and is still not perfectly understood. At excitatory synapses, AMPA receptors (AMPARs) are responsible for the fast synaptic transmission. With the recent developments in super-resolution microscopy, the community has changed its vision of synaptic transmission. One breakthrough was the discovery that AMPARs are not randomly distributed at synapses but are organized in nanodomains of ~80 nm of diameter containing ~20 receptors. This content is an important factor since it will determine the intensity of the synaptic response. Due to their mM affinity for glutamate, AMPARs can only be activated when located in an area of ~150 nm in front of the neurotransmitter release site. Recently, AMPAR nanodomains have been shown to be located in front of glutamate release sites and to form trans-synaptic nanocolumns at basal state. Thus, the nanoscale organization of AMPARs regarding release sites seems to be a key parameter for the efficiency of synaptic transmission. Another breakthrough in the field was the observation that AMPARs diffuse at the cell surface and are immobilized at synapses to participate to synaptic transmission. The dynamic exchange between AMPAR diffusive pool and the receptors immobilized into the nanodomains participates to maintain the efficiency of synaptic response upon high-frequency stimulation.The overall aim of my PhD has been to determine the role of each above listed parameters on the intimate properties of synaptic transmission both at basal state and during synaptic plasticity. First, we identified the crucial role of Neuroligin in the alignment of AMPAR nanodomains with glutamate release sites. In addition, we managed to break this alignment to understand its impact on synaptic transmission properties. In parallel, we demonstrated that, due to a decrease in their affinity for synaptic traps, desensitized AMPARs diffuse more at the plasma membrane than opened or closed receptors. This mechanism allows synapses to recover faster from desensitization and ensure the fidelity of synaptic transmission upon high-frequency release of glutamate. Finally, synapses can modulate their strength through long-term synaptic plasticity, in particular, Long-Term Depression (LTD) corresponds to a long-lasting weakening of synaptic strength and is thought to be important in some cognitive processes and behavioral flexibility through synapse selective elimination. Following the previous discoveries about the impact of AMPAR dynamic nano-organization at synapses on the regulation of the synaptic transmission strength and reliability, I decided to investigate their role in the weakening of synapses. I found that AMPAR nanodomain content drops down rapidly and this depletion last several minutes to hours. The initial phase seems due to an increase of endocytosis events, but in a second phase, AMPAR mobility is increased following a reorganization of the post-synaptic density. This change in mobility allows depressed synapses to maintain their capacity to answer to high-frequency inputs. Thus, we propose that LTD-induced increase in AMPAR mobility allows to conduct a reliable response in synapses under high-frequency stimulation and thus to selectively maintain them while eliminating the inactive ones.
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Benjamin Compans. Physiological role of AMPAR nanoscale organization at basal state and during synaptic plasticities. Human health and pathology. Université de Bordeaux, 2017. English. ⟨NNT : 2017BORD0700⟩. ⟨tel-01753429⟩

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