Descrizione del progetto
Organizzazione molecolare ed eccitabilità nei neuroni
I neuroni cerebrali possiedono l’incredibile abilità di integrare migliaia di input differenti in un singolo potenziale d’azione lungo l’assone. Tuttavia, l’organizzazione locale e l’interazione di proteine responsabili dell’eccitabilità neuronale non sono ancora stati chiariti in maniera esaustiva. Il progetto Nano-axo-syn, finanziato dall’UE, si avvarrà della microscopia a super risoluzione e dell’elettrofisiologia per caratterizzare l’organizzazione di molecole responsabili dell’integrazione dei segnali in ingresso e per decifrarne l’impatto sull’eccitabilità neuronale. Utilizzando un modello mulino di schizofrenia, gli scienziati studieranno modifiche strutturali potenziali e il modo in cui influiscono sull’output e sulla trasmissione neuronale in condizioni di malattia o di salute.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
WC2R 2LS London
Regno Unito