Cell-type Specific Mechanisms and Functional Consequences of Altered NMDA Receptor Development and Mecp2 Deficiency on Developing Cortical Circuits

Información del proyecto

NMDARETT

Identificador del acuerdo de subvención: 700999

DOI

10.3030/700999

Proyecto cerrado

Fecha de la firma de la CE 7 Marzo 2016

Fecha de inicio 1 Abril 2016

Fecha de finalización 2 Agosto 2018

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 195 454,80

Aportación de la UE

€ 195 454,80

Coordinado por

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Objetivo

NMDA receptor (NMDAR) dysfunction has been identified in multiple genetic causes of autism and related neurodevelopmental disorders. I recently showed that loss of Mecp2, the cause of Rett syndrome and some cases of autism, differentially affects NMDAR development at cortical synapses on specific cell-types: slowing down the development in excitatory pyramidal neurons and accelerating the maturation in parvalbumin-positive (PV) inhibitory interneurons. Genetic manipulation of NMDAR expression in Mecp2-deficient mice rescued both cortical function and the premature NMDAR maturation in PV cells. Based on these findings, I hypothesize that this cell-type specific disruption of NMDAR development leads to an imbalance in excitation and inhibition in the developing cortical circuits. To test this idea, I will combine single cell genomic and cell-type specific recording techniques to elucidate how Mecp2 controls the development of synaptic receptors and the impact on network function. In Aim 1, I will use cutting-edge techniques for single-cell RNA sequencing and synaptic recordings of NMDAR maturation in cortical cultures to identify novel cell-type specific mechanisms underlying NMDAR development and the regulation by Mecp2. In Aim 2, I will investigate the functional effects of Mecp2 deficiency and altered NMDAR maturation on the development of cortical network activity using two-photon calcium imaging and multi-electrode array (MEA) recordings. As a neuroscientist and neurologist, this training will prepare me for an independent research career addressing the circuit-based defects underlying Rett syndrome and autism. I have the full support of the University of Cambridge and Wellcome Trust Sanger Institute for the proposed research and my career development. This study will improve our understanding of how loss of Mecp2 alters cortical circuits and has the potential to identify novel cell-type specific targets for developing new therapies for Rett syndrome.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › neurobiología
• ciencias naturales › ciencias químicas › química inorgánica › metales alcalinotérreos
• ciencias médicas y de la salud › biotecnología médica › ingeniería genética
• ciencias naturales › ciencias biológicas › genética › ARN › transcriptomas

Palabras clave

• NMDA Receptors
• Rett Syndrome
• Development of excitatory synaptic transmission

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF)
  

Régimen de financiación

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

Convocatoria de propuestas

H2020-MSCA-IF-2015

Coordinador

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE

• Aportación neta de la UEn: € 195 454,80
• Dirección: TRINITY LANE THE OLD SCHOOLS ; CB2 1TN CAMBRIDGE ; Reino Unido
• Región: East of England › East Anglia › Cambridgeshire CC
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 195 454,80