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Cellular and molecular mechanisms controlling the integration of CGE interneurons into cortical circuits

Final Report Summary - INTRACORT (Cellular and molecular mechanisms controlling the integration of CGE interneurons into cortical circuits)

Understanding how brain function emerges through the assembly of specific neuronal circuits is one of the main challenges in neuroscience. In the cerebral cortex, excitatory glutamatergic pyramidal cells and inhibitory interneurons constitute the main cellular elements of neuronal circuits. Interneuron deficits seem to underlie a variety of neurodevelopmental and psychiatric disorders in humans, but our current knowledge of the mechanisms controlling their precise integration into cortical circuits remains very limited. The Marie Curie IEF INtraCort project (project #625730) aimed to determine the mechanisms mediating the allocation of interneurons born in the caudal ganglionic eminence (CGE) into circuits composed of pyramidal neurons and interneurons in the cerebral cortex.

We mapped the lamination of CGE interneurons born at different times (E13.5 E15.5 or E17.5) throughout the first post-natal week and P30. For all temporal cohorts, we observed a preferential lamination to superficial layers compared to deep layers. In contrast to Miyoshi et al., we found more early born CGE interneurons to populate deep layers compared to E15.5 CGE interneurons while the latter have a bigger preference for superficial layers compared to deep layers. These results demonstrate that E13.5 and E15.5 CGE INs follow an inside-out sequence of lamination, like medial ganglionic eminence (MGE) and pyramidal neurons do.

Two alternative hypotheses might explain CGE interneuron allocation: (i) CGE interneurons may adopt their location in response to pyramidal cells, as it is the case for MGE interneurons, or (ii) CGE interneurons allocate in the cortex influenced by MGE interneurons. To test whether MGE interneurons influence the allocation of CGE interneurons we investigated mouse mutants with defects in MGE interneurons. Aberrant development of MGE interneurons, results in an increase of CGE interneurons in deep layers at the expense of supragranular layer lamination. Preliminary results suggest that SST+ and not PV+ MGE interneurons instruct CGE lamination.

At the same time we focused on a subtype of CGE interneurons identified through VIP expression. It is suggested that lamination and development of axodendritic morphology of other CGE subtypes (Reelin+ and CR+), but not of VIP+ interneurons, depends on early activity in the cortical network. To identify the molecular mechanisms in VIP interneuron lamination we optimised isolation, dissociation and fluorescence-activated cell sorting (FACS) of these cells at different postnatal stages. RNA from these cells was used for RNA-sequencing and we are selecting genes for validation and functional testing during lamination of VIP+ CGE interneurons.

Together, these experiments will allow the dissection of the mechanisms underlying the precise integration of CGE interneurons into cortical circuits and contribute to our understanding of the aetiology of several neurodevelopmental and psychiatric disorders.