A nanoscale view into the dynamic of AMPA receptor organization in synapses
Ionotropic AMPA glutamate receptors (AMPAR) mediate fast excitatory synaptic transmission in the central nervous system. Using a combination of high resolution single molecule imaging techniques and video-microscopy, we have previously established that AMPARs are not stable in the synapse as thought initially, but undergo continuous entry and exit to and from the post-synaptic density through lateral diffusion. Single molecule approaches give access to the full distribution of molecule behaviors and overcome the averaging intrinsic to bulk measurement methods. They allow access to complex processes where a given molecule can have heterogeneous properties over time. We will present some recent developments in single molecule imaging technologies and their application to track single molecules in live neurons. We have recently found a new function for this fast diffusion in controlling fast synaptic transmission. Upon consecutive synaptic stimulation at high frequency, synaptic transmission is depressed. This depression shapes the frequency dependent adaptation of individual synapses. AMPAR lateral diffusion allows fast exchange of desensitised receptors with naïve functional ones within or nearby the post-synaptic density. This participates to the recovery from depression in the tens of millisecond time range, in parallel with recovery from desensitization. In addition, we now show that the Ca2+/Calmodulin-dependent protein kinase II (CaMKII), which is critically required for the synaptic recruitment of AMPA-type glutamate receptors (AMPARs) during both development and plasticity, induces the synaptic trapping of AMPARs diffusing in the membrane. Furthermore, this CaMKII dependent AMPAR immobilization regulates short term plasticity. Thus, NMDA dependent Ca2+ influx in the post-synapse trigger a CaMKII and Stargazin dependent decrease in AMPAR diffusional exchange at synapses that controls synaptic function.
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