A new paper, available now in eLife, reveals a novel strategy for the assembly of cortical circuits, involving differential subcellular sorting of family-related synaptic proteins. The elegant study, published by David Exposito-Alonso, Catarina Osório, Oscar Marín and Beatriz Rico, along with their colleagues from the Centre for Developmental Neurobiology, shows how subcellular sorting of synaptic proteins orchestrates the assembly of excitatory and inhibitory synapses in cortical circuits.

The assembly of neuronal circuits relies on the expression of complementary molecular programmes in presynaptic and postsynaptic neurons. Previous studies have shown that the tyrosine kinase receptor ErbB4 is required for the wiring of specific populations of GABAergic interneurons, in which it contributes to the formation of both excitatory inputs and inhibitory outputs.

In a series of genetic experiments, Exposito-Alonso et al. first analysed the role of Nrg1 and Nrg3 in the development of inhibitory synapses onto pyramidal cells. They then examined the function of neuregulins in the formation of inhibitory synapses by chandelier cells and analysed the number of parvalbumin positive (PV+) basket cell synapses contacting pyramidal cells lacking specific neuregulins. Finally, the authors examined the possible role of neuregulins in the assembly of excitatory synapses onto PV+ interneurons, since ErbB4 is located at these synapses and is essential for their formation.

Through their experiments, Exposito-Alonso et al. show that Nrg1 and Nrg3, two different members of the neuregulin family of trophic factors co-expressed by pyramidal cells, mediate the development of inhibitory synapses made and excitatory synapses received, respectively, by ErbB4-expressing cortical interneurons. The study highlights the crucial role of polarised protein trafficking for synaptic specificity in the formation of neuronal circuits and describes a novel strategy for the assembly of cortical circuits.