SYNarch · Understanding the nanoscale synaptome architecture of the brain
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2022-07-01 → 2024-06-30
- Финансиране от ЕС
- 212 934 €
- Участници
- 1
- Схема
- MSCA-IF
Линиите свързват координатора с партньорите.
Накратко на български
Наноструктурите на протеините в синапсите на мишки се изследват чрез специални микроскопични методи. Разбирането на тази организация помага да се разбере как генетични мутации влияят върху мозъка при състояния като аутизъм и шизофрения.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Understanding the nanoscale synaptome architecture of the brain
In the brain, neurons are connected by billions of synapses. The postsynaptic density (PSD) is a densely packed structure located beneath the postsynaptic membrane of excitatory synapses. PSD proteins play essential roles in synaptic structure and function, and their dysfunction is linked to more than 100 brain disorders, including schizophrenia, depression, autism, and intellectual disabilities. Key to PSD protein function is their assembly into complexes and supercomplexes, which are known to vary in composition and spatial distribution within synapses, contributing to synapse diversity. The Grant lab developed a pipeline for mapping synaptic complexes using high-speed confocal microscopy and advanced image analysis, revealing brain-wide synapse molecular diversity that changes throughout the lifespan in mice. At higher resolution, super-resolution microscopy showed that PSD95 proteins form nanoscale structures within synapses, adding nanoarchitecture as a further, as yet little understood, level to synapse diversity. These nanoscale arrangements are crucial for synaptic transmission and plasticity. Disease-associated mutations disrupt PSD supercomplex structures and synaptome architecture, particularly in models of autism and schizophrenia, but their impact on nanoarchitecture is unknown. The SYNarch project aimed to employ key PSD proteins to map diversity in synapse nanoarchitecture across regions of the mouse brain, providing a baseline for investigations into how mutations affect this fundamental level of synaptic protein organization, with implications for major brain disorders. During SYNarch, a method was developed to evaluate synaptic nanoarchitecture using Förster resonance energy transfer (FRET) between PSD95 molecules, which was combined with the synaptome mapping pipeline. This new combination of resolution and scale uncovered the diversity of synapse nanoarchitecture across brain regions and lifespan in mice, and probed the impact of a schizophrenia mutation.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Synapses play an essential role in all behaviours and damage to synapse proteins results in over a 130 brain disorders. The host Grant lab has developed methods for brain-wide mapping of protein composition at single-synapse resolution, uncovering unexpected diversity. The different synapse types show unique spatiotemporal distributions in the brain across the lifespan, which are altered in genetic models of autism and schizophrenia. Synapse proteins are assembled into multiprotein complexes and supercomplexes, but little is known about their composition and spatial organisation within individual synapses, particularly in the intact brain. In SYNarch I aim to understand this subsynaptic protein architecture, its contribution to the spatiotemporal organisation of synapse diversity, and alteration in disease. The work plan will deliver a depth of skill acquisition integrated across a range of cutting-edge biochemical, molecular imaging, ultrastructural and computational technologies. In WP1 I will optimise use of Förster resonance energy transfer (FRET) to probe the sub-10 nm spatial relationship and number of endogenously labelled PSD95 complexes within individual synapses, backed up by complementary super-resolution microscopy techniques (STORM, TIRF) and microfluidics analysis. In WP2, FRET will be integrated with synaptome mapping technology to deliver an atlas of nanoscale information on a brain-wide scale – the PSD nanoscale synaptome architecture (PNSA) of the mouse brain. In WP3 I will uncover how the PNSA is impacted in the Dlg2 schizophrenia mouse model. SYNarch will help to provide new molecular insight into brain function and dysfunction on an unprecedented scale.
Оригинален текст от CORDIS (на английски).
Участници
- THE UNIVERSITY OF EDINBURGH · EdinburghКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз