Dataset Information

Upregulation of ?3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway.

ABSTRACT: Synaptic scaling is a form of homeostatic plasticity driven 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 ? subunit (?3A) of the adaptor protein complex AP-3A. Synaptic scaling increased ?3A (but not other AP-3 subunits) in pyramidal neurons and redistributed dendritic ?3A and AMPAR to recycling endosomes (REs). Knockdown of ?3A prevented synaptic scaling and this redistribution, while overexpression (OE) of full-length ?3A or a truncated ?3A that cannot interact with the AP-3A complex was sufficient to drive AMPAR to REs. Finally, OE of ?3A acted synergistically with GRIP1 to recruit AMPAR to the dendritic membrane. These data suggest that excess ?3A 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.

SUBMITTER: Steinmetz CC

PROVIDER: S-EPMC5226429 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Steinmetz Celine C CC Tatavarty Vedakumar V Sugino Ken K Shima Yasuyuki Y Joseph Anne A Lin Heather H Rutlin Michael M Lambo Mary M Hempel Chris M CM Okaty Benjamin W BW Paradis Suzanne S Nelson Sacha B SB Turrigiano Gina G GG

Cell reports 20160825 10

Synaptic scaling is a form of homeostatic plasticity driven 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 (R ...[more]

PMID: 27568566

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Project description:Through substitution mapping studies, we previously identified that a <330kb region from a rat strain with no renal pathology (the Lewis rat), which when introgressed onto the genetic background of a rat with renal disease (the Dahl Salt-sensitive (S) rat), caused an increase rather than the expected decrease in proteinuria. The purpose of this study was to prioritize a candidate gene and further delineate the mechanism underlying the observed increased in proteinuria. A higher level of proteinuria independent of dietary salt was observed in the congenic rat at a very young age (50-52 day old). The critical congenic segment was further mapped to <42.5kb containing a single candidate gene, rififylin. Rififylin was expressed 1.59 fold higher in the congenic strain compared with S. Overexpression of rififylin is known to delay recycling of endosomes. Renal transcriptome analysis indicated that Atp1a1 one of the most highly differentially expressed genes. Atp1a1 was 5.33 fold higher in the congenic strain compared with S. The protein product of Atp1a1, the alpha subunit of Na+K+ATPase, was also significantly higher in the endosomes of proximal tubules from the congenic strain compared with S. To determine whether the higher amounts of this protein in the endosomes is due to a delay in recycling of endosomes caused by the overexpression of rififylin in the congenic strain, recycling of exogenously labeled-transferrin by single cell cultures of proximal tubules was monitored by confocal microscopy. Recycling of transferrin was significantly delayed in the congenic strain compared with S. These results suggest that impaired endosomal recycling in the proximal tubules from the congenic strain caused by the overexpression of rififylin is a novel molecular mechanism linked to the observed increase in proteinuria of the congenic strain. Three male S control and 3 male congenic S.LEW(10)x12x2x3x5 rats born on the same day were selected, weaned at 30 days of age, and caged with 1 congenic and 1 S rat per cage. They were raised on a low-salt (0.3%) diet (Harlan Teklad diet TD 7034; Harlan–Sprague-Dawley) and sacrificed at 53 days of age and total RNAs were isolated from the kidney. The isolated RNA from each animal was used for the cRNA preparation. cRNA was prepared and fragmented as suggested by Affymetrix technical manual, and simultaneously hybridized (15 µg adjusted cRNA for each chip) to Rat Expression Array 230 2.0 (3' IVT Expression Analysis). Statistical analyses of the microarray data were performed with BH adjustment using R statistical package (version 2.8.1).

Dataset Information

Upregulation of ?3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway.

Publications

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

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