Upregulation of μ3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway

Celine C Steinmetz,Vedakumar Tatavarty,Ken Sugino,Yasuyuki Shima,Anne Joseph,Heather Lin,Michael Rutlin,Mary Lambo,Chris M Hempel,Benjamin W Okaty,Suzanne Paradis,Sacha B Nelson,Gina G Turrigiano

doi:10.1016/j.celrep.2016.08.009

Celine C Steinmetz, Vedakumar Tatavarty + Show 11 more

Open Access

https://doi.org/10.1016/j.celrep.2016.08.009

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Journal: Cell Reports	Publication Date: Aug 25, 2016
Citations: 22	License type: cc-by

Affiliation: Brandeis University

Abstract

Synaptic scaling is a form of homeostatic plasticitydriven by transcription-dependent changes in AMPA-type glutamate receptor (AMPAR) trafficking. To uncover the pathways involved, we performed a cell-type-specific screen for transcripts persistently altered during scaling, which identified the μ subunit (μ3A) of the adaptor protein complex AP-3A. Synaptic scaling increased μ3A (but not other AP-3 subunits) in pyramidal neurons and redistributed dendritic μ3A and AMPAR to recycling endosomes (REs). Knockdown of μ3A prevented synaptic scaling and this redistribution, while overexpression (OE) offull-length μ3A or a truncated μ3A that cannot interact with the AP-3A complex was sufficient to drive AMPAR to REs. Finally, OE of μ3A acted synergistically with GRIP1 to recruit AMPAR to the dendritic membrane. These data suggest that excess μ3A acts independently of the AP-3A complex to reroute AMPAR to RE, generating a reservoir of receptors essential for the regulated recruitment to the synaptic membrane during scaling up.

Highlights

The ability of networks to maintain stable function over time, and to efficiently store information, is thought to rely on homeostatic plasticity mechanisms that stabilize neuronal and network activity (Davis, 2013; Turrigiano and Nelson, 2004)
We set out to devise an unbiased screen for factors that are persistently upregulated during synaptic scaling in the hopes of gaining deeper insight into the transcription-dependent AMPA-type glutamate receptor (AMPAR) trafficking pathways involved in this critical form of synaptic plasticity
The ex vivo slice and profiling studies were conducted on HsCt5 mice at postnatal day (P) 14 to P15, an age at which synaptic scaling can be induced within layer 4 (L4) star pyramidal neurons by 2 days of optic nerve blockade using intraocular TTX (Figure 1A; Desai et al, 2002)

Summary

Introduction

The ability of networks to maintain stable function over time, and to efficiently store information, is thought to rely on homeostatic plasticity mechanisms that stabilize neuronal and network activity (Davis, 2013; Turrigiano and Nelson, 2004). Several studies have examined the transcriptional changes within extracts of V1 following visual deprivation protocols (Lachance and Chaudhuri, 2004; Majdan and Shatz, 2006; Tropea et al, 2006) These earlier studies probed tissue derived from total V1, including all cell types and all layers. This is problematic, because synaptic scaling is expressed in a cell-type- and layer-specific manner (Desai et al, 2002; Maffei and Turrigiano, 2008); this approach does not provide the necessary sensitivity to isolate transcripts that are involved in synaptic scaling. Two days of visual deprivation via intraocular tetrodotoxin (TTX) injection induces synaptic scaling up of miniature excitatory postsynaptic currents (mEPSCs) onto layer 4 (L4) star pyramidal neurons in rodent

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Conclusion