15/05/25
New work published in Nature Communications from the Rico lab has significantly advanced our understanding of the molecular mechanisms that govern neuronal connectivity in the cerebral cortex. The landmark study, led by Julie Jézéquel from the Rico lab, has identified the crucial role of cadherins in orchestrating specific patterns of perisomatic inhibition among distinct populations of pyramidal cells during development.
Neuronal connectivity is essential for brain function, influencing everything from primal behaviour to complex cognitive processes. GABAergic interneurons were previously thought to form unselective connections with various pyramidal cells. However, recent research has highlighted the existence of a cell type-specific inhibitory connectome, which is crucial for the precise regulation of excitatory networks.
Julie Jézéquel and colleagues identified two cadherin superfamily members, Cdh12 and Cdh13, as pivotal for establishing cell type- and input-specific inhibitory patterns in layer 5 (L5) pyramidal cell populations. Using a combination of retrograde tracing, RNA sequencing and viral genetic manipulations, the authors demonstrated that L5 intra-telencephalic (L5 IT) and extra-telencephalic (L5 ET) neurons exhibit unique transcriptional programs that shape their inhibitory wiring. They found that Cdh12 and Cdh13 are enriched in L5 IT and L5 ET neurons, respectively, and that this differential expression enables the differentiation of inhibitory inputs from parvalbumin-positive (PV+) and cholecystokinin-positive (CCK+) interneurons onto distinct pyramidal cell types.
The group’s findings suggest that these cadherins play a significant role in the development of inhibitory microcircuits, essential for proper brain function. Disruptions in these patterns could have implications for the way we conceptualise neurodevelopmental disorders and open new avenues for exploring therapeutic targets in these conditions.
Read the full study in Nature Communications
Image supplied by Julie Jézéquel and the Rico lab
