L.Groc, S.Oliet, C. Murphy-Royal et al. inNat Neurosci.
Transporters on the Move !!
Surface diffusion of astrocytic glutamate transporters shapes synaptic transmission. Murphy-Royal C, Dupuis JP, Varela JA, Panatier A, Pinson B, Baufreton J, Groc L, Oliet SH. Nat Neurosci. 2015 Feb;18(2):219-26. doi: 10.1038/nn.3901. Epub 2015 Jan 12.
Transporters on the Move !!
Understanding how the astrocytic transporters of glutamate are localized in the vicinity of synapses has been a longstanding challenge in the field of neuroscience. It is indeed crucial for a given excitatory synapse to control the clearance of glutamate to ensure optimal synaptic communication under physiological conditions, and to prevent the accumulation of the neurotransmitter in the extracellular space, a process that could lead to excitotoxicity as it is the case in many neurological disorders.
How transporters are trafficked to the synaptic area and what happens if this mobility is altered? To tackle these challenging questions, several Bordeaux labs have joined forces (CNRS IINS, INSERM Magendie, CNRS IBGC, CNRS IMN), under the drive of a highly talented PhD student, Ciaran Murphy-Royal who was part of the EDU-Glia Marie Curie ITN. Thanks to the local support of the Labex Brain and Trail, we coupled single nanoparticle tracking and electrophysiological approaches to discover that glutamate transporters are highly dynamics at the plasma membrane of astrocytes. Strikingly, this diffusive behavior plays a key role in clearing synaptic glutamate and thus shapes the fast glutamatergic transmission.
Transporters are thus not static complex, but rather “super marathonians”, whose running activity is essential for optimizing the buffering of extracellular glutamate! We will continue this collaborative effort between our two labs (Groc/Oliet) to dig further into the physiological meaning of this discovery. In addition, this work surely opens conceptually new avenues of research for innovative therapeutics, and we will try to tackle this challenge together with clinician collaborators.
Control of the glutamate time course in the synapse is crucial for excitatory transmission. This process is mainly ensured by astrocytic transporters, high expression of which is essential to compensate for their slow transport cycle. Although molecular mechanisms regulating transporter intracellular trafficking have been identified, the relationship between surface transporter dynamics and synaptic function remains unexplored. We found that GLT-1 transporters were highly mobile on rat astrocytes. Surface diffusion of GLT-1 was sensitive to neuronal and glial activities and was strongly reduced in the vicinity of glutamatergic synapses, favoring transporter retention. Notably, glutamate uncaging at synaptic sites increased GLT-1 diffusion, displacing transporters away from this compartment. Functionally, impairing GLT-1 membrane diffusion through cross-linking in vitro and in vivo slowed the kinetics of excitatory postsynaptic currents, indicative of a prolonged time course of synaptic glutamate. These data provide, to the best of our knowledge, the first evidence for a physiological role of GLT-1 surface diffusion in shaping synaptic transmission.
“News and Views”
Cette publication a bénéficié d’un News ans Views dans Nature !
Nat Neurosci. 2015 Jan 27;18(2):166-8. doi: 10.1038/nn.3931.
Mobile binding sites regulate glutamate clearance.
Departments of Physiology and Neurology, University of California, San Francisco, San Francisco, California, USA.
Thèse de Juin 2014
Titre: La diffusion de surface du transporteur astrocytique du glutamate GLT-1 contrôle la transmission synaptique
Directeurs de thèse: Laurent Groc (IINS)
et Stéphane Oliet (Neurocentre)
Last update : 2015/01/29