The actin-modulating protein Synaptopodin mediates long-term survival of dendritic spines

Yap, Kenrick; Drakew, Alexander; Smilovic, Dinko; Rietsche, Michael; Vukšić, Mario; Turco, Domenico Del; Deller, Thomas

doi:10.1101/2020.05.08.080374

Cited by 8 publications

(14 citation statements)

References 66 publications

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“…Dendritic spines of all shapes were assessed manually on z ‐stacks of dendritic segments in the OML. Only protrusions emanating laterally in the x ‐ y directions, not above or below the dendrite, and exceeding the dendrite for at least 5 pixels (0.2 μm) were included for analysis (Holtmaat et al., 2009; Vlachos, Müller‐Dahlhaus, et al., 2012; Yap et al., 2020). The length of each segment was determined (Figure 3a).…”

Section: Methodsmentioning

confidence: 99%

Constitutive tumor necrosis factor (TNF)‐deficiency causes a reduction in spine density in mouse dentate granule cells accompanied by homeostatic adaptations of spine head size

Smilovic

Rietsche

Drakew

et al. 2021

J of Comparative Neurology

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The majority of excitatory synapses terminating on cortical neurons are found on dendritic spines. The geometry of spines, in particular the size of the spine head, tightly correlates with the strength of the excitatory synapse formed with the spine. Under conditions of synaptic plasticity, spine geometry may change, reflecting functional adaptations. Since the cytokine tumor necrosis factor (TNF) has been shown to influence synaptic transmission as well as Hebbian and homeostatic forms of synaptic plasticity, we speculated that TNF‐deficiency may cause concomitant structural changes at the level of dendritic spines. To address this question, we analyzed spine density and spine head area of Alexa568‐filled granule cells in the dentate gyrus of adult C57BL/6J and TNF‐deficient (TNF‐KO) mice. Tissue sections were double‐stained for the actin‐modulating and plasticity‐related protein synaptopodin (SP), a molecular marker for strong and stable spines. Dendritic segments of TNF‐deficient granule cells exhibited ∼20% fewer spines in the outer molecular layer of the dentate gyrus compared to controls, indicating a reduced afferent innervation. Of note, these segments also had larger spines containing larger SP‐clusters. This pattern of changes is strikingly similar to the one seen after denervation‐associated spine loss following experimental entorhinal denervation of granule cells: Denervated granule cells increase the SP‐content and strength of their remaining spines to homeostatically compensate for those that were lost. Our data suggest a similar compensatory mechanism in TNF‐deficient granule cells in response to a reduction in their afferent innervation.

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Section: Methodsmentioning

confidence: 99%

Constitutive tumor necrosis factor (TNF)‐deficiency causes a reduction in spine density in mouse dentate granule cells accompanied by homeostatic adaptations of spine head size

Smilovic

Rietsche

Drakew

et al. 2021

J of Comparative Neurology

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“…Previous reports showed that the presence of synaptopodin assemblies is necessary for the stability and long-term survival of dendritic spines (Okubo-Suzuki et al, 2008;Yap et al, 2020b).…”

Section: Discussionmentioning

confidence: 99%

“…Neuronal synaptopodin specifically localizes to dendritic spines and to the axonal initial segment where another specialization of the ER similar to the spine apparatus (stack of flattened cisterns) called the cisternal organelle, is present (Bas Orth et al, 2007;Deller et al, 2000;Sánchez-Ponce et al, 2012;Vlachos, 2012). Lack of synaptopodin in synaptopodin KO mice correlates with lack of SA and of the cisternal organelle, as well as with a reduction in Hebbian plasticity and spatial memory (Bas Orth et al, 2007;Deller et al, 2003Deller et al, , 2007Vlachos et al, 2009;Yap et al, 2020a).…”

Section: Introductionmentioning

confidence: 99%

Properties and proximity proteomics of synaptopodin provide insight into the molecular organization of the spine apparatus of dendritic spines

Falahati

Feuerer

et al. 2021

Preprint

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The spine apparatus is a specialization of the neuronal ER in dendritic spines consisting of stacks of interconnected cisterns separated by a dense matrix. Synaptopodin, a specific actin binding protein of the spine apparatus, is essential for its formation, but the underlying mechanisms remain unknown. We show that synaptopodin, when expressed in fibroblasts, forms actin-rich structures with connections to the ER, and that an ER-tethered synaptopodin assembles into liquid condensates. We also identified protein neighbors of synaptopodin in spines by in vivo proximity biotinylation. We validated a small subset of such proteins and showed that they co-assemble with synaptopodin in living cells. One of them is Pdlim7, an actin binding protein not previously identified in spines, and we show its precise colocalization with synaptopodin. We suggest that the matrix of the spine apparatus has the property of a liquid protein condensate generated by a multiplicity of low affinity interactions.

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“…Spines containing sER, and presumably Synpo, possess higher synaptic strength (Holbro et al, 2009). Moreover spines harboring Synpo undergo slower constitutive turnover and as such are more stable compared to mushroom spines in which Synpo is absent (Yap et al, 2020). By analogy, in the preparation used here, mGluR-LTD appears to promote loss of spines that are ‘weaker’ and ‘unstable’ vs .…”

Section: Discussionmentioning

confidence: 99%

Stabilization of spine Synaptopodin by mGluR1 is required for mGluR-LTD

Speranza

Inglebert²,

Sanctis

et al. 2021

Preprint

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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. Post-mGluR-LTD, mushroom spines lacking Synaptopodin/SA are selectively lost whereas spines harboring it are preserved, a process dependent on activation of mGluR1 but not mGluR5. 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.

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The actin-modulating protein Synaptopodin mediates long-term survival of dendritic spines

Cited by 8 publications

References 66 publications

Constitutive tumor necrosis factor (TNF)‐deficiency causes a reduction in spine density in mouse dentate granule cells accompanied by homeostatic adaptations of spine head size

Constitutive tumor necrosis factor (TNF)‐deficiency causes a reduction in spine density in mouse dentate granule cells accompanied by homeostatic adaptations of spine head size

Properties and proximity proteomics of synaptopodin provide insight into the molecular organization of the spine apparatus of dendritic spines

Stabilization of spine Synaptopodin by mGluR1 is required for mGluR-LTD

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