miR‐124‐dependent tagging of synapses by synaptopodin enables input‐specific homeostatic plasticity

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.

Antiepileptic medication strengthens excitatory neurotransmission in pyramidal neurons of the adult human neocortex

“…As a result, this study provides evidence for local homeostatic synaptic adjustment within the human neocortex. Our experiments corroborate previous findings, confirming that the inhibition of voltage-gated sodium channels triggers homeostatic synaptic plasticity across various brain regions (Turrigiano et al, 1998; Sutton et al, 2006; Dubes et al, 2022; Kavalali and Monteggia, 2023). Importantly, this plasticity arises within unaffected brain regions of healthy mouse brain tissue and in human brain tissue samples from patients, which received antiepileptic medication.…”

Synaptopodin regulates denervation-induced plasticity at hippocampal mossy fiber synapses

“…We here demonstrate that synaptopodin and the spine apparatus organelle represent dendritic ribosomal hubs that contribute to plasticity-driven local protein synthesis. The lesion-induced ultrastructural remodeling of the spine apparatus organelle might therefore represent a novel regulatory mechanism for localized changes in synaptic transmission (Dubes et al, 2022;Vlachos et al, 2009). Notably, we found opposing plasticity phenomena at hippocampal mossy fiber synapses on the level of individual neuron pairs in wildtype and synaptopodin-deficient tissue preparations where synaptopodin deficiency did not only cause defects in plasticity expression but hampered the ability of neurons to maintain synaptic stability upon lesion.…”

“…We here demonstrate that synaptopodin and the spine apparatus organelle represent dendritic ribosomal hubs that contribute to plasticity-driven local protein synthesis. The lesion-induced ultrastructural remodeling of the spine apparatus organelle might therefore represent a novel regulatory mechanism for localized changes in synaptic transmission (Vlachos et al, 2009; Dubes et al, 2022).…”

Synaptic tagging: homeostatic plasticity goes Hebbian

“…In this study, Dubes et al (2022) tackle two major questions with regard to local, input‐specific HSP: first, do excitatory synapses, much like in Hebbian plasticity, scale dependent on their previous activation history? Second, what might be the molecular mechanism, or “tag,” which marks synapses for preferential scaling?…”

“…The neuron‐enriched miR‐124 was reported to downregulate SP in the spinal cord, thereby representing an obvious candidate. Using reporter gene assays, Dubes et al (2022) were able to validate SP as a direct target of miR‐124 in neurons. They went on to show that TTX induces downregulation of miR‐124, whereas miR‐124 overexpression occludes the TTX‐mediated increase in SP‐positive spines, synaptic AMPARs, and mEPSCs.…”