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Transmembrane AMPAR regulatory protein γ-2 is required for the modulation of GABA release by presynaptic AMPARs.

Rigby, M; Cull-Candy, SG; Farrant, M; (2015) Transmembrane AMPAR regulatory protein γ-2 is required for the modulation of GABA release by presynaptic AMPARs. Journal of Neuroscience , 35 (10) 4203 - 4214. 10.1523/JNEUROSCI.4075-14.2015. Green open access

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Abstract

Presynaptic ionotropic glutamate receptors (iGluRs) play important roles in the control of synaptogenesis and neurotransmitter release, yet their regulation is poorly understood. In particular, the contribution of transmembrane auxiliary proteins, which profoundly shape the trafficking and gating of somatodendritic iGluRs, is unknown. Here we examined the influence of transmembrane AMPAR regulatory proteins (TARPs) on presynaptic AMPARs in cerebellar molecular layer interneurons (MLIs). 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a partial agonist at TARP-associated AMPARs, enhanced spontaneous GABA release in wild-type mice but not in stargazer mice that lack the prototypical TARP stargazin (γ-2). These findings were replicated in mechanically dissociated Purkinje cells with functional adherent synaptic boutons, demonstrating the presynaptic locus of modulation. In dissociated Purkinje cells from stargazer mice, AMPA was able to enhance mIPSC frequency, but only in the presence of the positive allosteric modulator cyclothiazide. Thus, ordinarily, presynaptic AMPARs are unable to enhance spontaneous release without γ-2, which is required predominantly for its effects on channel gating. Presynaptic AMPARs are known to reduce action potential-driven GABA release from MLIs. Although a G-protein-dependent non-ionotropic mechanism has been suggested to underlie this inhibition, paradoxically we found that γ-2, and thus AMPAR gating, was required. Following glutamate spillover from climbing fibers or application of CNQX, evoked GABA release was reduced; in stargazer mice such effects were markedly attenuated in acute slices and abolished in the dissociated Purkinje cell-nerve bouton preparation. We suggest that γ-2 association, by increasing charge transfer, allows presynaptic AMPARs to depolarize the bouton membrane sufficiently to modulate both phasic and spontaneous release.

Type: Article
Title: Transmembrane AMPAR regulatory protein γ-2 is required for the modulation of GABA release by presynaptic AMPARs.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.4075-14.2015
Publisher version: http://dx.doi.org/10.1523/JNEUROSCI.4075-14.2015
Language: English
Additional information: Copyright © 2015 the authors. This article is freely available online through the J Neurosci Author Open Choice option.
Keywords: AMPA receptor, IPSC, cerebellum, glutamate, molecular layer interneurons, neurotransmitter release
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/1464925
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