Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • Synaptic scaling up is induced within primary visual cortex

    2022-12-01

    Synaptic scaling up is induced within primary visual N6022 (V1) by brief sensory deprivation (Desai et al., 2002; Lambo and Turrigiano, 2013). 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). However, 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); therefore, this approach does not provide the necessary sensitivity to isolate transcripts that are specifically involved in synaptic scaling. For this reason, we designed a screen that would allow us to probe for transcriptional changes in a defined population of pyramidal neurons in which we know synaptic scaling is induced. 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 visual cortex during early postnatal development (Desai et al., 2002). Here we generated a mouse with mCitrine expressed within these L4 star pyramids, allowing us to probe for transcriptional changes in this specific cell population (Sugino et al., 2006). This highly targeted approach revealed a relatively small number of transcripts (30) with expression changes that reached the criterion (fold change > 1.5, p < 0.0034) following visual deprivation. Surprisingly, two of these, Ap3m1 and Ap4m, code for μ subunits (μ3A and μ4, respectively) of the heterotetrameric clathrin adaptor protein (APC) complexes AP-3 and AP-4. The APC family is composed of five members (AP-1 through AP-5) that sort and shuttle membrane-bound cargo between different endosomal and cell-surface compartments (Faúndez et al., 1998; Hirst et al., 2013; Le Borgne et al., 1998; Nakatsu and Ohno, 2003; Newell-Litwa et al., 2007; Robinson and Bonifacino, 2001; Simpson et al., 1997); the μ subunits are critical for most cargo recognition (Bonifacino and Traub, 2003; Mardones et al., 2013; Ohno et al., 1998; Traub and Bonifacino, 2013). Although none of these complexes were previously known to have activity-regulated expression, several of them have been implicated in basal sorting and trafficking of glutamate receptors (Margeta et al., 2009; Kastning et al., 2007; Lee et al., 2002). In particular, μ3A and μ4 can bind AMPAR indirectly through interactions with transmembrane AMPR regulatory proteins (TARPs) (Matsuda et al., 2008, 2013), and this interaction is important for dendritic trafficking of AMPAR (Matsuda et al., 2008) and for N-methyl-D-aspartate (NMDA)-induced trafficking of internalized AMPAR from early endosomes (EEs) to lysosomes (AP-3; Matsuda et al., 2013). These considerations suggest that μ3A could contribute to the regulated trafficking of AMPAR that underlies synaptic scaling up (Kennedy and Ehlers, 2006; Turrigiano, 2008). Here we show that μ3A upregulation plays an essential role in synaptic scaling up by trafficking GluA2-containing AMPAR into the recycling pathway. AP-3 is classically known for sorting membrane proteins into the lysosomal pathway for degradation (Bonifacino and Traub, 2003), so it was surprising to find that TTX treatment rerouted μ3A from lysosomes to recycling endosomes (REs). Both TTX treatment and overexpression (OE) of μ3A were able to drive AMPAR into the RE pathway, as was OE of a truncated μ3A that cannot interact with the rest of the AP-3 complex (Mardones et al., 2013). Furthermore, knockdown (KD) of μ3A, which blocks the normal increase in μ3A induced by activity blockade, prevented the activity-dependent rerouting AMPAR to REs and blocked synaptic scaling. Finally, OE of μ3A acted synergistically with the GluA2 trafficking protein GRIP1 to recruit AMPAR to the dendritic surface. Taken together, these data show that activity blockade transcriptionally upregulates μ3A to reroute AMPAR into the RE pathway and is essential for the recruitment of AMPAR to the cell surface during synaptic scaling up (Figure S1).