Team leader : Alessandra Pierani
Team member : Patrick Azzam | Pierre Billuart | Frédéric Causeret | Driss El Ouardi | Vicente Elorriaga Benavides | Sofia Ferreira | Matthieu Moreau | Nassim Ramezanidoraki | Yoann Saillour | Lisa Vigier
Cognitive functions depend on the precise construction of complex neural circuits which begins during early embryonic development. Studies in the past decades have revealed that abnormal brain development participates to the aetiology of multiple neurological and psychiatric disorders including intellectual disability, epilepsy, schizophrenia, autism spectrum disorders, obsessive-compulsive behaviors and bipolar disorders.
Our work has shown that proper cortical development depends on the action of different cell types that are transiently present during the construction of neural circuits. We reported that transient variations in the kinetics of arrival of these migrating signalling neurons during early development, or of their death at the end of corticogenesis have profound consequences on the construction of normal and pathological neural circuits. These transient signalling neurons express at high levels genes whose mutations have been associated with neurological and psychiatric disorders. At the earliest stages of corticogenesis in mice, long before any functional synapses are formed, these neurons express genes that are involved in neurotransmission and are thought to be exclusively present at mature synapses. We have published and unpublished data showing that these genes control neuronal migration during embryogenesis. Our recent results in primates and chick also suggest that an increase in both number and diversity of transient neurons might represent an evolutionary addition to wire higher-order cortical areas in the cerebral cortex and to increase vertebrate brain complexity and cognitive function.
By coupling studies on the function and dysfunction of transient neuron development in mice and primates, our future projects aim at linking developmental neuroscience with evolution and pathology in humans. In particular, they aim at i) molecularly dissecting how transient migratory neurons serve as organizers in neocortical development, ii) determining how the acquisition of these neurons in mammals has contributed to the evolution of the neocortex and iii) testing how manipulating their number, migration and survival affects neural circuits in mouse models and may lead to pathological conditions. We employ a multidisciplinary approach including mouse genetics (cell tracing and ablation, gene knock-out), pharmacological and genetic manipulation during embryogenesis using in vitro and in utero paradigms including electroporation, together with transcriptome profiling, phenotyping using behavioural tests and migration studies using single-cell resolution and time-lapse microscopy. Furthermore, in collaboration, we also use electrophysiology, optogenetics and mathematical modelling.
Our projects span from early onset cortical malformations to susceptibility to later-onset diseases characteristic of psychiatric illnesses. We have joined the Institute of Psychiatry and Neurosciences of Paris (IPNP, Hôpital St Anne, Paris) and also the Institute Imagine (Institut des Maladies Génétiques, Hôpital Necker Enfants malades, Paris) to develop this translational project in collaboration with neuroscientists, human geneticists and clinicians. This will allow closer interactions with human geneticists and clinical experts in rare diseases, brain imaging and malformations.
# equal contribution, underlined corresponding authors