Abstract
Synaptic scaling is a form of homeostatic plasticity that is critical for maintaining neuronal activity within a dynamic range, and which alters synaptic strength through changes in postsynaptic AMPA-type glutamate receptors. Homeostatic scaling down of excitatory synapses has been shown to occur during sleep, and to contribute to synapse remodeling and memory consolidation, but the underlying mechanisms are only partially known. Here, we report that synaptic downscaling in cortical neurons is accompanied by dephosphorylation of the transmembrane AMPA receptor regulatory protein stargazin, and by an increase in its cell surface mobility. The changes in stargazin surface diffusion were paralleled by an increase in the mobility of GluA1-containing AMPA receptors at synaptic sites. In addition, stargazin dephosphorylation was required for the downregulation of surface levels of GluA1-containing AMPA receptors promoted by chronic elevation of neuronal activity, specifically by mediating the interaction with the adaptor proteins AP-2 and AP-3A. Disruption of the stargazin-AP-3A interaction was sufficient to prevent the decrease in cell surface GluA1-AMPA receptor levels associated with chronically enhanced synaptic activity, suggesting that scaling down is accomplished through decreased AMPA receptor recycling and enhanced lysosomal degradation. Thus, synaptic downscaling is associated with both increased stargazin and AMPA receptor cell surface diffusion, as well as with stargazin-mediated AMPA receptor endocytosis and lysosomal degradation.
Highlights
Homeostatic synaptic scaling protects information coding in the brain by allowing neurons to keep neuronal activity within a physiological range while constantly facing destabilizing changes in synaptic strength
To test whether stargazin dephosphorylation and increased mobility associated with synaptic downscaling are accompanied by alterations in the cell surface mobility of GluA1-containing AMPA receptors, we evaluated the diffusion coefficient of endogenous GluA1-AMPA receptors using an antibody against an extracellular epitope in GluA1 (Figure 3A)
We uncover an important role for stargazin dephosphorylation in synaptic downscaling of cortical synapses
Summary
Homeostatic synaptic scaling protects information coding in the brain by allowing neurons to keep neuronal activity within a physiological range while constantly facing destabilizing changes in synaptic strength. Synaptic scaling was initially described in cultured neocortical neurons, after pharmacological manipulation of activity elicited compensatory and bidirectional changes in the strength of glutamatergic synapses through AMPA receptor accumulation (Turrigiano et al, 1998). Alterations in the signaling mediated by group I metabotropic glutamate receptors (Hu et al, 2010; Diering et al, 2017), by PKA (Diering et al, 2014), phosphatase PP1 activation (Siddoway et al, 2013) and secreted semaphoring 3F (Wang et al, 2017) contribute to synaptic downscaling. Ubiquitination of AMPA receptor subunits and their proteasomal and/or lysosomal degradation are implicated (Hou et al, 2011; Scudder et al, 2014), and the synaptic removal of the scaffold protein PSD-95 is required for scaling down (Sun and Turrigiano, 2011), through a mechanism that involves Ca2+/calmodulin binding to the N-terminus of PSD-95 (Zhang et al, 2014; Chowdhury et al, 2018)
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