Alessandra Pierani

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 epilepsy, schizophrenia, autism spectrum disorders, obsessive-compulsive behaviors and bipolar disorders.

Our work has shown that proper cortical development also depends on the action of different cell types that are transiently present during the construction of 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 in the cerebral cortex, 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 We have published and unpublished data showing that “synaptic” genes, whose mutations have been associated with pathological conditions, control neuronal migration during embryogenesis. Our recent results in primates also suggest that an increase in both number and diversity of migrating transient signalling neurons could be an evolutionary addition to wire higher-order cortical areas in the cerebral cortex and to increase vertebrate brain complexity and cognitive function.

Our data show 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. We have shown that changes in neuronal migration during embryonic life lead to dysfunctional cortical circuits spanning from severe neonatal cortical malformations to subtle and transient defects, which mimics diseases with onset at puberty/adolescence. 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.

Our projects span from early onset cortical malformations to susceptibility to later-onset diseases characteristic of psychiatric illnesses. They are now reaching the stage where we wish to, and can, ask questions relevant to human health. Thus, we have decided to join the Institute Imagine (Institut des Maladies Génétiques, Hôpital Necker Enfants malades, Paris) and the Institute of Psychiatry and Neurosciences of Paris (IPNP, Hôpital St Anne, Paris) to be able to develop this translational project in collaboration with neuroscientists, human geneticists and clinicians. Our Team moved in September 2017 and is reinforced by 4 people holding permanent positions (two researchers, one Engineer and one MD). This allows closer interactions with human geneticists and clinicical experts in rare diseases, brain imaging and malformations. Our team’s strong expertise in cortical development will introduce a novel dimension fostering synergistic interactions across disciplinary boundaries. Our future projects should provide new genetic tools to develop mouse models for cortical abnormalities and contribute to the understanding and diagnosis of neurodevelopmental diseases in humans.