How do cell types achieve their precise connectivity in the cerebral cortex? Really excited that our latest research @Rico_lab and @MarinLab on molecular mechanisms of cortical circuit assembly is now out in @eLife. (1/9) https://doi.org/10.7554/eLife.57000

Pyramidal cells and interneurons make up the intricate wiring of the cerebral cortex and establish excitatory and inhibitory synapses with remarkable precision by expressing an amalgam of molecules involved in #synapse formation during #brain development. (2/9)

We were stunned to find that the deletion from cortical pyramidal cells of two family-related proteins, neuregulin 1 and neuregulin 3, causes specific deficits in their inhibitory synaptic inputs and excitatory synaptic outputs, respectively. (3/9)

And gain-of-function experiments in vivo increase the formation of the two different types of cortical synapses with the same selectivity: Nrg1 drives inhibitory synapses innervating pyramidal cells, and Nrg3 enhances excitatory synapses contacting interneurons. (4/9)

To our surprise, we found that Nrg1 and Nrg3 localize to different subcellular compartments in cortical pyramidal cells: Nrg1 is restricted to their perisomatic compartment, and Nrg3 is targeted to their axon terminals. (5/9)

We designed structure-function analyses to find protein domains that play a role in such specific subcellular function. Swapping the EGF-like domain taught us that the extracellular region isn’t responsible for the specificity of Nrg1 and Nrg3 in cortical synapses. (6/9)

When we swapped the C-terminal domains, we discovered that the cytoplasmic tails of Nrg1 and Nrg3 instruct their precise subcellular distribution and allow a differential control over the two types of synapses - excitatory vs inhibitory. (7/9)

With striking selectivity, the role of molecules in building different synaptic connections can be specified by their subcellular distribution in cortical neurons. Research on the key function of Nrg/ErbB4 signalling in cortical connectivity continues to surprise us. (8/9)

Huge thanks to my colleagues in the lab for an outstanding work @NeurOsorio @clembrnrd @hipatia08 @DelPino_Isabel. And especially to my PhD advisors Beatriz @Rico_lab and Oscar @MarinLab for the amazing training over the past years! @dev_neuro @MRC_CNDD @KingsIoPPN (9/9)