H2020Индивидуална стипендия2020–2022

Nano-axo-syn · Nanoscale organisation of axo-axonic synapses along the axon initial segment of cortical pyramidal neurons in health and disease.

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-05-01 → 2022-04-30
Финансиране от ЕС: 212 934 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Разположението на протеините в специалните връзки между невроните се изучава чрез анализа на протеина гефирин. Разбирането на тези структури помага да се разбере как се регулират сигналите в мозъка и при кои нарушения, като шизофренията, този процес е променен.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Nanoscale organisation of axo-axonic synapses along the axon initial segment of cortical pyramidal neurons in health and disease.

Synapses in the central nervous system are highly specialized structures dedicated to the transfer of information from one neuron to another. Each neuron receives thousands of excitatory and inhibitory synaptic inputs along their dendrites, that are integrated at the axon initial segment (AIS) to generate a new electrical signal called an Action Potential. Regulation of this fundamental process is key for proper brain function and was shown to be altered in several neurodevelopmental pathologies such as schizophrenia and autism spectrum disorder. Interestingly, the AIS of pyramidal neurons (PNs) is innervated by a specific type of inhibitory interneuron, a Chandelier cell. Although these axo-axonic synapses are thought to be capable of tightly regulating AP initiation, their structural and functional properties remain largely unexplored. At classical synapses formed along dendrites, the molecular organisation of synaptic proteins at the nanoscale is a key factor in fine- tuning the efficiency of synaptic transmission. However, the precise nanoscale arrangement of molecules at axo-axonic synapses has not been previously characterised, nor its impact on the modulation of pyramidal neuron firing. Here, we have shown that key proteins such as Gephyrin, the main scaffolding protein of inhibitory synapses, forms subsynaptic domains (SSD) at axo-axonic synapses. These SSDs display different properties, in term of size and density of proteins, when compared to dendritic synapses, which are formed by different types of interneurons. In addition, using genetic tools to chronically increase neuronal activity of PNs in the somatosensory cortex in vivo, we have shown that the nanoscale organisation of gephyrin is plastic. We are currently assessing the functional impact of this intriguing plasticity. Our findings provide a potential mechanism by which Chandelier cells synapse tune their strength to control PN output.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Neurons in the brain have extensive dendritic arbours that receive thousands of synaptic inputs all along it. The transformation of all these inputs to an output in a single neuron occurs through the integration of synaptic events and the generation of an action potential (AP) at the axon initial segment (AIS). The AIS, therefore, is the site that controls neuronal output by gating the generation of APs. It has been recently shown that this neuronal compartment can be reorganized following a change in neuronal activity and that this structural plasticity is associated with a change in neuronal excitability. In addition, the AIS of pyramidal neurons is innervated by a specific type of inhibitory interneuron, a Chandelier cell, that forms axo-axonic connections specifically with it. Therefore, the AIS can be seen as a short stretch of axon that brings together molecules critical for AP initiation (e.g. - voltage-gated channels) and synaptic proteins essential for the local modulation of excitability. The interplay between these two compartments at the nanoscale level is not known. At classical excitatory and inhibitory synapses, the nanoscale molecular organisation of synaptic proteins has been shown to be a key factor in modulating the efficiency of synaptic transmission between neurons. However, the precise molecular organisation of axo-axonic synapses is still poorly understood, as is its role in regulating neuronal output. We propose to decipher this organisation in mouse brain slices using the state-of-the-art super-resolution microscopy combined with electrophysiology. Once the nanoscopic arrangement elucidated, we will study how it is modified during activity-dependent forms of plasticity and how this, in turn, leads to changes in neuronal excitability. Finally, we will establish how this neuronal output hub is organized in a mouse model of schizophrenia in which synaptic transmission between pyramidal neurons and Chandelier cells is altered.

Оригинален текст от CORDIS (на английски).

Участници

KING'S COLLEGE LONDON · LondonКоординаторОбединеното кралство