Research

Brains are composed of a multitude of neuronal cell types that assemble together into functional circuits. In mammals, and particularly in humans, the neocortex is the centre of higher cognitive functions and hosts some of the most complex and poorly elucidated neuronal circuits. Our lab is interested in how these complex neuronal circuits are formed during development:

• How does this large diversity of cells emerge?
• How does each cell type mature?
• How do they come together to form functional networks?

We focus on the development of GABAergic inhibitory neurons in the cortex – one of the most diverse population neurons. This large repertoire of inhibitory cells is thought to increase network performance by fine-tuning the activity of cortical circuits in space and time, thus allowing for novel forms of computations.

Interneurons play a central role in cortical function and disease. Understanding their diversity is essential to decipher circuit assembly and design new cell replacement therapies for brain disorders. Emerging evidence indicates that metabolic transitions drive cell differentiation. Our own data show that interneuron progenitors from the ventricular zone express glycolytic genes more strongly compared to those in the subventricular zone, which have a restricted fate potential. These changes in metabolism can operate on a rapid timescale and could, in principle, poise progenitors towards specific lineages.

That is why we believe that distinct metabolic states alter cell cycle dynamics of progenitors and drive interneuron diversification. Our central goal is to identify metabolic states in interneuron progenitors that specify cell fate and lineage diversification.

The majority of cortical inhibitory neurons project locally and have thus been classified as interneurons. Local inhibition of excitatory outputs by interneurons is at the basis of all current models of cortical function, and disruption of these local inhibitory circuits has been implicated in a range of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy.

However, not all cortical GABAergic neurons are locally projecting cells. An estimated 10% of these cells project over long distances both within and outside the cortex. Despite their first description over a decade ago, surprisingly, little is known about the development and functions of GABAergic projection neurons in the neocortex. We study the molecular and functional diversity of long-range GABAergic neurons and the gene networks that shape their development.

Despite the identification of numerous genes linked to Autism Spectrum Disorder (ASD), there is at present no clear understanding of the molecular, cellular and circuit defects that cause ASD. We study the function of a prominent ASD-associated gene, reelin, in the context of inhibitory circuits in the developing neocortex.

Reelin is a pivotal gene in cortical development, and it is also strongly implicated in ASD, with now more than 40 different mutations linked to disease. We want to unravel the precise developmental trajectory of cortical inhibitory circuits in ASD, in the hope to facilitate the identification of new targets for therapeutic interventions.