Cholinergic and NMDAR-dependent recruitment of Layer 1 Interneuron shapes cortical motor Processing through network States Modulation

Projektinformationen

InProSMod

ID Finanzhilfevereinbarung: 892175

DOI

10.3030/892175

Projekt abgeschlossen

EK-Unterschriftsdatum 12 März 2020

Startdatum 1 September 2021

Enddatum 28 Februar 2024

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 196 707,84

EU-Beitrag

€ 196 707,84

Koordiniert durch

INSTITUT DU CERVEAU ET DE LA MOELLE EPINIERE
France

Periodic Reporting for period 1 - InProSMod (Cholinergic and NMDAR-dependent recruitment of Layer 1 Interneuron shapes cortical motor Processing through network States Modulation)

Berichtszeitraum: 2021-09-01 bis 2023-08-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Brain disorders are one of the greatest health challenges. It is estimated that around 30% of Europeans will suffer from a neurological and/or mental disorder at some point in their live. Given their immense socio-economic impact, it is therefore crucial to find new treatments for brain disorders.
However, cognition in the healthy brain relies on a tremendous complexity at the cellular and circuit levels. Part of this complexity resides in the presence of diverse interneuronal circuits that enable inhibitory interactions between brain modules. One such circuit is the inhibitory network found in the most superficial layer of the cortex (Layer 1, L1) that is strongly driven by contextual information from higher order brain modules (i.e. top-down signals).
In this project, I characterized the synaptic and circuit properties underlying the top-down control of cortical networks by L1 interneurons. My analysis revealed that the activity of L1 interneurons was strongly dependent on the N-methyl-D-aspartate receptor (NMDAR). Next, I found that normal sensorimotor function was dependent on L1 integration and was impaired upon deletion of the NMDAR in L1 interneurons. Those results therefore emphasized the important contribution of the cellular mechanisms (here the NDMAR) in L1 interneurons in shaping cortical processing in the healthy brain. Importantly, this study points to a new therapeutic target for NMDAR-related diseases such as schizophrenia or depression: L1 interneurons. By suggesting new therapeutic approaches for NMDAR-related disease, the fundamental knowledge generated in this action could therefore have crucial implications for brain disorders.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

In this project, I characterized the synaptic and circuit properties of L1 interneurons combining experimental characterization and theoretical analysis. I found that L1 interneurons had a very strong component mediated by the N-methyl-D-aspartate receptor (NMDAR) in synaptic transmission. Next, I found that normal sensorimotor function was dependent on L1 integration and was impaired upon deletion of the NMDAR in L1 interneurons.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

This action has substantially improved our knowledge on the role of interneurons in cortical processing. Notably, it emphasized the important contribution of the cellular mechanisms (here the NDMAR) in L1 interneurons in shaping cortical processing in the healthy brain. Most importantly, this study points to a new therapeutic target for NMDAR-related diseases such as schizophrenia or depression: L1 interneurons. The fundamental knowledge generated in this action could therefore have crucial implications for brain disorders and therefore strongly reduce their socio-economic impact.

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