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 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.
Metabolic Mechanisms Driving Neuronal Diversification and Cortical Circuit Assembly
How interneuron diversity arises during development is not well understood and highly debated. Given the central involvement of interneurons in cortical functions and diseases, a molecular and system-based understanding of interneuron diversity is key to decipher the cellular logic of cortical circuit assembly and to design novel cell replacement therapies for brain disorders.
Emerging evidence from various systems have shown that metabolic transitions can operate as instructive cues during cell differentiation. From our own data, we find that interneuron progenitors from the ventricular zone (VZ) show higher expression of glycolytic genes compared to those in the subventricular zone (SVZ), 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. Based on these preliminary data, we posit 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.
Assembly and diversity of long-range inhibitory circuits in the brain
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, this model is likely to be incomplete because not all cortical GABAergic neurons are locally projecting cells. An estimated 10% of these cells project over long distances both within (cortico-cortical projections) and outside the cortex (cortico-striatal projections). Despite their first description over a decade ago, surprisingly, little is known about the development and functions of GABAergic projection neurons in the neocortex.
Our previous work provides a compelling entry point to examine the development of long-range GABAergic neurons. While characterizing the migration patterns of SST+ cells during mouse embryonic cortical development, we showed that distinct subclasses of SST+ interneurons use different tangential migratory streams, either along the marginal zone (MZ) or subventricular zone (SVZ), to reach the cortex.
Our results further revealed that long-range SST+ cells mainly migrate along the SVZ route, in contrast to locally projecting SST+ cells (Martinotti) that take the MZ route. This marked difference in migration behaviour suggests that SST+ projection neurons display a unique developmental trajectory. In a parallel effort, our lab has started to comprehensively analyse SST+ subtypes at distinct developmental stages by scRNAseq. In this project, we will (1) define the molecular and functional diversity of long-range GABAergic neurons and (2) to identify the gene networks that shape their development.
Role of Reelin in Interneuron in Cortical Development and Disease
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. The lack of a clear endophenotype significantly hinders the development of disease-modifying therapeutics. This proposal aims at bridging this gap by interrogating 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. The reelin gene (RELN) is also strongly implicated in ASD, with now more than 40 different mutations linked to disease. Emerging evidence points to a vulnerable window in early development of the cerebral cortex, coinciding with RELN expression, during which environmental or genetic insults increase risk for ASD (Fatemi et al., 2005a, 2009). In the cortex, RELN is highly expressed in GABAergic inhibitory interneurons, a diverse cell class consisting of a multitude of subtypes, thus complicating the identification of RELN-expressing neurons implicated in ASD. By combining single cell RNAsequencing with available data on the function of reelin in corticogenesis, we were able to narrow the expression of reelin during the ASD vulnerability window to a single relevant subtype of cortical interneurons – somatostatin positive (SST+) Martinotti cells. These preliminary findings suggest that early defects in SST+/Martinotti cells may drive ASD pathogenesis, in line with a growing body of evidence implicating cortical interneurons in ASD.
We hypothesize that impaired reelin expression in SST+/Martinotti cells during early corticogenesis perturbs axonal development of these cells and results in synaptic and circuits defects that contribute to ASD. Specifically, we will (i) examine the cell-autonomous function of RELN in the development and maturation of SST+ interneurons, and (ii) to determine changes in inhibitory circuits resulting from specific ablation of RELN in SST+ interneurons. To this end, we have generated a mouse line with specific ablation of RELN in SST+ interneurons (SSTcre; RELN fl/fl). The proposed research promises to unravel the precise developmental trajectory of a cortical inhibitory circuit implicated in ASD and should facilitate the identification of new targets for therapeutic interventions.