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

Project Information

InProSMod

Grant agreement ID: 892175

DOI

10.3030/892175

Project closed

EC signature date 12 March 2020

Start date 1 September 2021

End date 28 February 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 196 707,84

EU contribution

€ 196 707,84

Coordinated by

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)

Reporting period: 2021-09-01 to 2023-08-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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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