Equipe 4 : Mécanismes du développement cérébral (Gaspar / Métin)

Team leader : Patricia Gaspar (DR1 INSERM)

Neural circuits have exquisite organizations that underlie all integrated brain functions. The correct assembly of these neural circuits during development involves a complex sequence of events, including neuronal migration, axon growth, axon branching and synaptogenesis. These processes are both genetically determined and modulated by environmental cues/neuronal activity during critical periods of development. Perturbations of these developmental processes are thought to be involved in the pathophysiology of a number of neurological and psychiatric disorders, such as epilepsy, autism, or anxiety disorders.

In our team, we investigate molecular mechanisms involved in neuronal migration and neural circuit wiring, focusing on 3 model systems: 1) Cortical interneuron migration; 2) wiring of the visual system ; 3) Developmental role of serotonin.

Cortical migration of interneurons: Role of Sonic Hedgehog and of the primary cilium
PI : Christine Métin

The cortical GABAergic neurons are inhibitory interneurons that play an essential role in cortical function to control neuronal excitability. Altered development of interneurons have been implicated in pathologies such as epilepsy, mental retardation, and schizophrenia. During embryonic life, interneurons migrate over long distances before reaching the cortex as they are generated outside the cortex in ventral forebrain regions called the ganglionic eminences. We have previously demonstrated that GABA interneurons assemble a primary cilium during their migration and that this cilium is involved in the direction of migratory trajectories by mechanisms that are still unknown. Moreover, Sonic Hedgehog (Shh) influences the migration of interneurons in part via signal transduction at the cilium.

Our current projects aim to understand how Shh and the primary cilium control the migration of GABA interneurons and the establishment of local inhibitory circuits. (transcriptional regulation, local signaling, etc). Beside studies in mouse mutants, we are using in vitro approaches to further characterize the influence of biochemical and physical factors on the migratory properties of interneurons.

FigureChM 3

Figure 1 : (A) Scheme of a coronal section from the left hemisphere of a mouse embryo illustrating the trajectories of GABAergic neurons born in the medial ganglionic eminence (MGE) toward the developing cortex: tangential migration pathways in blue and green, radial trajectories in yellow. (B) Immunostaining (in green) of the primary cilium of a MGE neuron (in red) migrating on a substrate of cortical cells (nuclei in blue). (C) A genetic ablation of the primary cilium or an application of cyclopamine (Sonic hedgehog –SHH- pathway inhibitor) maintains MGE neurons in their tangential migration pathway, whereas an application of SHH promotes their exit from the tangential pathway (From Pedraza & Métin, 2014).

Development of visual pathways, implication in albinism
PI : Alexandra Rebsam

Images that are processed in the retina are transmitted to the brain via retinal ganglion cells (RGCs) that form maps in visual brain centers such as the superior colliculus and the lateral geniculate nucleus (the visual thalamus). Retinotopic maps are point to point projections of the RGCs to these brain centers and underlie visual function. Other superimposed maps are the eye-specific maps, which underlie the integration of information from both eyes to ensure stereoscopic vision. We study the role of axon guidance molecules such as the semaphorins and the plexins in the establishment of these maps; Moreover, we study the impact of mutations involved in genetic diseases such as albinism on the organization of these maps. In humans and rodents carrying albino mutations, the retinal circuits do not develop normally and the eye-specific retinal maps are disorganized leading to visual defects. However, the mechanisms are still unknown.

Our approaches combine mouse genetics with tract tracing and molecular developmental approaches. In addition in vitro stem cell approaches are being developed to study disease physiopathology.

For more information see : www.rebsam.org

Developmental role of serotonin
PI : Patricia Gaspar

Serotonin (5-HT) systems have been involved in the pathophysiology of many disorders in particular in psychiatry. The 5-HT transporter is the main target of antidepressants that act by increasing 5-HT levels at the synapse. In addition to its function in the adult brain, 5-HT has an important developmental role, as it can modulate multiple developmental processes from neurogenesis to synaptogenesis. We have previously demonstrated a role of 5-HT in the development of sensory maps. We are now analyzing the role of 5-HT in the development of prefrontal circuits, and aim to understand how 5-HT neurotransmission might interact with the effects of early life stressors to modify brain circuits. In parallel, we analyze the development of the 5-HT raphé neurons, trying to tease out the contribution of the different raphé nuclei in behaviors controlled by 5-HT.
We use genetically modified mice and a range of morphological/ molecular approaches in vivo and in vitro.

Team Composition

Team leaders : Patricia Gaspar (DR1 INSERM) et Christine Métin (DR2 INSERM)
• Alexandra Rebsam CR2 INSERM
• Christine Laclef MC UPMC
• Sophie Scotto MC UPMC
• Aude Muzerelle IE INSERM
• Maria Pedraza Boti Post-doctorante
• Mariano Soiza Relly Post Doctorant
• Anne Teissier Post doctorante
• Claire Leclech Doctorante
• Teng Teng Doctorant
• Delphine Prieur Doctorante
• Jimmy Olusakin Doctorant
• Akindé Lawrence-stagiaire M1.