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

Projektbeschreibung

Molekulare Organisation und Erregbarkeit in Neuronen

Die Neuronen im Gehirn besitzen die bemerkenswerte Fähigkeit, Tausende unterschiedliche Inputs in einem einzigen Aktionspotenzial entlang des Axons zu integrieren. Die lokale Organisation und Wechselbeziehung der Proteine, die für die neuronale Erregbarkeit verantwortlich sind, wurden bisher jedoch nicht vollständig erforscht. Das EU-finanzierte Projekt Nano-axo-syn wird mithilfe von superauflösender Mikroskopie und Elektrophysiologie die Organisation der Moleküle, die für die Integration des Inputs zuständig sind, charakterisieren und entschlüsseln, inwieweit sie an der neuronalen Erregbarkeit beteiligt sind. Anhand eines Mausmodells für Schizophrenie werden die Projektforschenden strukturelle Modifikationen erforschen und untersuchen, wie diese sich auf den neuronalen Output und die neuronale Übertragung im gesunden und kranken Zustand auswirken.

Ziel

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.

Koordinator

KING'S COLLEGE LONDON
Netto-EU-Beitrag
€ 212 933,76
Adresse
STRAND
WC2R 2LS London
Vereinigtes Königreich

Auf der Karte ansehen

Region
London Inner London — West Westminster
Aktivitätstyp
Higher or Secondary Education Establishments
Links
Gesamtkosten
€ 212 933,76