MiR‐124‐dependent tagging of synapses by synaptopodin enables input‐specific homeostatic plasticity. (25th July 2022)

• Record Type: Journal Article
• Authors: Dubes, Sandra; Soula, Anaïs; Benquet, Sébastien; Tessier, Béatrice; Poujol, Christel; Favereaux, Alexandre; Thoumine, Olivier; Letellier, Mathieu
• Is Part Of: EMBO journal. Volume 41:Number 20(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-25
• Subjects: homeostatic synaptic plasticity -- microRNA -- synaptopodin -- synaptic tag -- synapse‐autonomous; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021109012
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Homeostatic synaptic plasticity is a process by which neurons adjust their synaptic strength to compensate for perturbations in neuronal activity. Whether the highly diverse synapses on a neuron respond uniformly to the same perturbation remains unclear. Moreover, the molecular determinants that underlie synapse‐specific homeostatic synaptic plasticity are unknown. Here, we report a synaptic tagging mechanism in which the ability of individual synapses to increase their strength in response to activity deprivation depends on the local expression of the spine‐apparatus protein synaptopodin under the regulation of miR‐124. Using genetic manipulations to alter synaptopodin expression or regulation by miR‐124, we show that synaptopodin behaves as a "postsynaptic tag" whose translation is derepressed in a subpopulation of synapses and allows for nonuniform homeostatic strengthening and synaptic AMPA receptor stabilization. By genetically silencing individual connections in pairs of neurons, we demonstrate that this process operates in an input‐specific manner. Overall, our study shifts the current view that homeostatic synaptic plasticity affects all synapses uniformly to a more complex paradigm where the ability of individual synapses to undergo homeostatic changes depends on their own functional and biochemical state. Synopsis: Homeostatic synaptic plasticity is a process by which synaptic strength is adjusted to compensate for prolonged activity perturbations. This study demonstrates that the differential ability of synapses to compensate for activity deprivation results in non‐uniform homeostatic synaptic plasticity, in which some synapses but not others are primed to undergo homeostatic changes. Dendritic spines containing synaptopodin are larger, contain more AMPA receptors, and display higher ability to potentiate upon global activity deprivation. Local translation of synaptopodin is enhanced upon activity deprivation and occurs preferentially at large vs. small synapses. HSP can be implemented in a synapse‐specific manner and is accompanied by a local increase of synaptopodin expression. HSP induced globally or at single synapses requires miR‐124‐mediated local derepression of synaptopodin translation. Abstract : Selective regulation of synaptopodin expression at synapses allows for the capture of surface‐diffusing AMPA receptors to support homeostatic synaptic plasticity.