Molecular regulation of circuit assembly in the cerebral cortex

Abstract

The cerebral cortex harbours an intricate network of interconnected cell types that is essential for sensory perception and cognitive function. The assembly of specific synaptic connections in neuronal circuits requires the expression of complementary molecular programs in pre and postsynaptic neurons. The tyrosine kinase receptor ErbB4 is critical for the wiring of specific types of GABAergic interneurons, in which it paradoxically regulates both the formation of perisomatic inhibitory synapses as well as the development of excitatory synapses received by these cells. Neuregulins, the ligands of ErbB4 receptor, play essential roles during brain development and synapse formation, yet their precise function in the wiring of cortical circuits during postnatal development remains unclear. Here we investigated the logic whereby Nrg1 and Nrg3 expression in pyramidal cells mediates ErbB4-dependent functions in cortical synaptic assembly. We found that Nrg1 and Nrg3 have segregated functions in the formation of inhibitory and excitatory synapses that pyramidal cells receive from or establish onto different types of interneurons, respectively. The differential role of Nrg1 and Nrg3 in this process is not due to a differential trans-synaptic interaction with ErbB4 through their EGF-like domain, but rather to their distinctive subcellular distribution within pyramidal cells. Nrg1 is restricted to the perisomatic region of pyramidal cells, whereas Nrg3 is precisely targeted to the presynaptic glutamatergic boutons that these cells make onto cortical interneurons. Our experiments reveal how the regulation of subcellular localisation underlies the function of the neuregulin/ErbB4 signalling pathway in specific synaptic connections. These findings uncover a novel strategy for the assembly of cortical circuits during postnatal development that involves the differential subcellular sorting of family-related synaptic proteins.

Date of Award	1 Jan 2021
Original language	English
Awarding Institution	King's College London
Supervisor	Beatriz Rico (Supervisor) & Oscar Marin (Supervisor)