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  • Title: Stabilization of Spine Synaptopodin by mGluR1 Is Required for mGluR-LTD.
    Author: Speranza L, Inglebert Y, De Sanctis C, Wu PY, Kalinowska M, McKinney RA, Francesconi A.
    Journal: J Neurosci; 2022 Mar 02; 42(9):1666-1678. PubMed ID: 35046120.
    Abstract:
    Dendritic spines, actin-rich protrusions forming the postsynaptic sites of excitatory synapses, undergo activity-dependent molecular and structural remodeling. Activation of Group 1 metabotropic glutamate receptors (mGluR1 and mGluR5) by synaptic or pharmacological stimulation, induces LTD, but whether this is accompanied with spine elimination remains unresolved. A subset of telencephalic mushroom spines contains the spine apparatus (SA), an enigmatic organelle composed of stacks of smooth endoplasmic reticulum, whose formation depends on the expression of the actin-bundling protein Synaptopodin. Allocation of Synaptopodin to spines appears governed by cell-intrinsic mechanisms as the relative frequency of spines harboring Synaptopodin is conserved in vivo and in vitro Here we show that expression of Synaptopodin/SA in spines is required for induction of mGluR-LTD at Schaffer collateral-CA1 synapses of male mice. Post-mGluR-LTD, mushroom spines lacking Synaptopodin/SA are selectively lost, whereas spines harboring it are preserved. This process, dependent on activation of mGluR1 but not mGluR5, is conserved in mature mouse neurons and rat neurons of both sexes. Mechanistically, we find that mGluR1 supports physical retention of Synaptopodin within excitatory spine synapses during LTD while triggering lysosome-dependent degradation of the protein residing in dendritic shafts. Together, these results reveal a cellular mechanism, dependent on mGluR1, which enables selective preservation of stronger spines containing Synaptopodin/SA while eliminating weaker ones and potentially countering spurious strengthening by de novo recruitment of Synaptopodin. Overall, our results identify spines with Synaptopodin/SA as the locus of mGluR-LTD and underscore the importance of the molecular microanatomy of spines in synaptic plasticity.SIGNIFICANCE STATEMENT Long-term changes in functional synaptic strength are associated with modification of synaptic connectivity through stabilization or elimination of dendritic spines, the postsynaptic locus of excitatory synapses. How heterogeneous spine microanatomy instructs spine remodeling after long-term synaptic depression (LTD) remains unclear. Metabotropic glutamate receptors mGluR1 and mGluR5 induce a form of LTD critical to circuit function in physiological and disease conditions. Our results identify spines containing the protein Synaptopodin, which enables local assembly of a spine apparatus, as the locus of expression of mGluR-LTD and demonstrate a specific role of mGluR1 in promoting selective loss after mGluR-LTD of mature dendritic spines lacking Synaptopodin/spine apparatus. These findings highlight the fundamental contribution of spine microanatomy in selectively enabling functional and structural plasticity.
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