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Nathalie Rouach "Role of TARP in the regulation of hippocampal AMPA receptors"

Abstract :


S
ynaptic plasticity involves activity dependent trafficking of AMPA type glutamate receptors. Numerous cytoplasmic scaffolding proteins are postulated to control AMPA receptor trafficking, but the detailed mechanisms remain unclear. The first transmembrane protein found to interact with AMPA receptors, stargazin, which is mutated in stargazer mice, controls the synaptic targeting and functioning of AMPARs in cerebellar granule cells by multiple mechanisms(1,2). Stargazin interacts with AMPARs early in the synthetic pathway, ensures their proper maturation and promotes their surface expression(3). Stargazin also binds to the scaffolding protein PSD-95, and this interaction translocates surface AMPARs to the synapse(2,4). The defects in AMPAR trafficking in stargazer mice appear restricted to cerebellar granule cells, as synaptic transmission in hippocampus is normal1.
Among a large family of stargazin related proteins, a subset (g-3, g-4, g-8) the transmembrane AMPAR regulatory proteins (TARPs), can rescue the AMPAR defects in stargazer cerebellar granule cells(3). g-8 has high sequence homology with stargazin; however, g-8 also has two unique domains in the C-terminal tail. TARPs are differentially distributed in the brain(3), raising the possibility that they either function similarly in different brain areas or have distinct properties. However, no direct evidence exists demonstrating a critical role for TARPs in AMPAR trafficking outside of the cerebellum. To address these issues we investigated the role of the TARP g-8, which is preferentially expressed in the hippocampus. We found that TARP g-8 is important for AMPA receptor protein levels and extrasynaptic surface expression5. By controlling the number of AMPA receptors, g-8 has also an important role in synaptic plasticity.
This establishes g-8 as a critical protein for basal AMPA receptor expression and localization at extrasynaptic sites in the hippocampus and raises the possibility that TARP dependent control of AMPA receptors during synapse development and plasticity may be widespread. 

Selected publications

Rouach, N. et al.
TARP gamma-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity. Nature Neuroscience (in press) (2005).
Tomita, S. et al.
Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins.
J Cell Biol 161, 805-16 (2003).
Schnell, E. et al.
Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number.
Proc Natl Acad Sci U S A 99, 13902-7 (2002).
Chen, L. et al.
Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms.
Nature 408, 936-43. (2000).
Hashimoto, K. et al.
Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer.
J Neurosci 19, 6027-36 (1999).

Stéphane Oliet