PROJECT: JTC2021: ROSSINI

peRsistence Of tranSient neuronS In Neurodevelopmental dIsorders

Abstract

Abnormal cortical development underlies the pathophysiology of multiple neurodevelopmental disorders (NDDs). Programmed cell death (PCD) is emerging as a key player in cortical development. Three neuronal populations almost completely disappear from postnatal neocortex, including Cajal-Retzius neurons (CRs). Persistence of CRs in postnatal cortex and hippocampus is detected in various forms of epilepsy and schizophrenia. We produced the first mouse model in which CRs survive to adulthood and showed they display neuronal hypertrophy and unbalanced excitatory/inhibitory ratio, leading to dysfunction of cortical circuits and increased seizure susceptibility. We will explore how persistent CRs contribute to anomalous activities underlying NDDs. Specifically, we will study i) CR evolution in the developing human cortex and their altered PCD in NDDs associated with epilepsy, ii) how anomalous CR persistence influences neuronal and network activity to promote rhythmopathies and epilepsy, iii) the molecular mechanisms underlying PCD of various CR subtypes and their alteration in the pathology. Our project relies on a unique blend of human and mouse studies involving molecular genetics, single-cell transcriptomics, in vitro and in vivo electrophysiology, functional assays and behavioral phenotyping. It will both lead to development of new mouse models for cortical malformations and identification of new candidate genes for analysis of human pathology and therapeutic intervention.

Keywords

Gene targeting in the brain, Epilepsy, Molecular modelling techniques, Imaging techniques, Electrophisiological approaches, Behavioural methodologies, (epi)genetic approaches, omics approaches, Patient cohorts, Animal studies, neurodevelopment disorders, programmed cell death, transient neurons, Chloride homeostasis

Call topic

Neurodevelopmental Disorders

Proposed runtime

n/a - n/a

Project team

Alessandra Pierani (Coordinator)
France (ANR)
Eleonora Aronica
Other Country (own funds)
Jean-Christophe Poncer
France (ANR)
Liset De la Prida
Spain (AEI)
Heiko Luhmann
Germany (BMBF)