A brain atlas of synapse protein lifetime across the mouse lifespan

Bulovaite, Edita; Qiu, Zhen; Kratschke, Maximilian; Zgraj, Adrianna; Fricker, David; Tuck, Eleanor J.; Gokhale, Ragini; Koniaris, Babis; Jami, Shekib A.; Merino‐Serrais, Paula; Husi, Elodie; Mendive‐Tapia, Lorena; Vendrell, Marc; O’Dell, Thomas J.; DeFelipe, Javier; Komiyama, Noboru H.; Holtmaat, Anthony; Fransén, Erik; Grant, Seth G. N.

doi:10.1016/j.neuron.2022.09.009

Cited by 44 publications

(73 citation statements)

References 107 publications

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“…Furthermore, the half-life of PSD95 in SPL synapses is around one to two weeks 1 , which corresponds well with the duration of synaptome repair in Pax6 +/− mice. These results, together with the dynamic changes in the synaptome and in the turnover of synaptic proteins across the lifespan 1,2 , indicate that the capacity to remodel the molecular identity of synapses is a property of all regions of the brain.…”

Section: Discussionmentioning

confidence: 89%

“…PSD95 and SAP102 are two of the four paralogous members of the MAGUK family and their levels are functionally important because they physically assemble multiple proteins controlling synaptic transmission, plasticity and neuronal excitability into macromolecular complexes [28][29][30][31] , and altering their expression leads to changes in synaptic and cognitive functions 32,33 . Previously, we have characterized mice carrying engineered alleles of endogenous PSD95 and SAP102 in a wide range of biochemical, anatomical, physiological and behavioral studies [1][2][3][28][29][30][32][33][34][35][36][37][38][39][40][41] . Here we used mice that have been engineered to express the fluorescent proteins eGFP and mKO2 attached to the carboxyl terminus of PSD95 and SAP102, respectively, which enable visualization of synaptic puncta 2,3 .…”

Section: Resultsmentioning

confidence: 99%

“…We recently found that PSD95-expressing excitatory synapse subtypes differ greatly in their rate of protein turnover, indicating that some subtypes can more rapidly remodel their proteomes 1 . We hypothesized that these synapse subtypes could be capable of mediating the phenotype waves observed in Pax6 +/− mice.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

“…Excitatory synapses, which make up the vast majority of synapses in the brain, have highly diverse identities resulting from their differing protein composition and protein lifetimes [1][2][3] . The anatomical distribution of these molecularly diverse synapses can be studied using synaptome mapping technology, a large-scale, single-synapse resolution, systematic image analysis approach that has uncovered brainwide excitatory synapse diversity in the mouse [1][2][3] . The Mouse Lifespan Synaptome Atlas 2 revealed that the synapse composition of the brain changes continuously across the lifespan, with trajectories of excitatory synapse types and subtypes in dendrites, neurons, circuits and brain regions, together defining the Lifespan Synaptome Architecture (LSA) 2 .…”

mentioning

confidence: 99%

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Developmental disruption and restoration of brain synaptome architecture in the Pax6 neurodevelopmental disease model

Tomás‐Roca

Qiu

Fransen

et al. 2022

Preprint

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Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. However, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse diversity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with network and cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synapse diversity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders.

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Section: Discussionmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Developmental disruption and restoration of brain synaptome architecture in the Pax6 neurodevelopmental disease model

Tomás‐Roca

Qiu

Fransen

et al. 2022

Preprint

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Small Fluorogenic Amino Acids for Peptide‐Guided Background‐Free Imaging

et al. 2022

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The multiple applications of super‐resolution microscopy have prompted the need for minimally invasive labeling strategies for peptide‐guided fluorescence imaging. Many fluorescent reporters display limitations (e.g., large and charged scaffolds, non‐specific binding) as building blocks for the construction of fluorogenic peptides. Herein we have built a library of benzodiazole amino acids and systematically examined them as reporters for background‐free fluorescence microscopy. We have identified amine‐derivatized benzoselenadiazoles as scalable and photostable amino acids for the straightforward solid‐phase synthesis of fluorescent peptides. Benzodiazole amino acids retain the binding capabilities of bioactive peptides and display excellent signal‐to‐background ratios. Furthermore, we have demonstrated their application in peptide‐PAINT imaging of postsynaptic density protein‐95 nanoclusters in the synaptosomes from mouse brain tissues.

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Chemical Approaches to Optimize the Properties of Organic Fluorophores for Imaging and Sensing

Jiang,

Liu,

Liu

et al. 2023

Angewandte Chemie

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Organic fluorophores are indispensable tools in cells, tissue and in vivo imaging, and have enabled much progress in the wide range of biological and biomedical fields. However, many available dyes suffer from insufficient performances, such as short absorption and emission wavelength, low brightness, poor stability, small Stokes shift, and unsuitable permeability, restricting their application in advanced imaging technology and complex imaging. Over the past two decades, many efforts have been made to improve these performances of fluorophores. Starting with the luminescence principle of fluorophores, this review clarifies the mechanisms of the insufficient performance for traditional fluorophores to a certain extent, systematically summarizes the modified approaches of optimizing properties, highlights the typical applications of the improved fluorophores in imaging and sensing, and indicates existing problems and challenges in this area. This progress not only proves the significance of improving fluorophores properties, but also provide a theoretical guidance for the development of high‐performance fluorophores.

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A brain atlas of synapse protein lifetime across the mouse lifespan

Cited by 44 publications

References 107 publications

Developmental disruption and restoration of brain synaptome architecture in the Pax6 neurodevelopmental disease model

Developmental disruption and restoration of brain synaptome architecture in the Pax6 neurodevelopmental disease model

Small Fluorogenic Amino Acids for Peptide‐Guided Background‐Free Imaging

Chemical Approaches to Optimize the Properties of Organic Fluorophores for Imaging and Sensing

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