Neuregulin-4 Is Required for Maintaining Soma Size of Pyramidal Neurons in the Motor Cortex.

Blanca Paramo,Isabel Martinez-Garay,Sven O Bachmann,Alun M Davies,Stéphane J Baudouin

doi:10.1523/eneuro.0288-20.2021

Abstract

The regulation of neuronal soma size is essential for appropriate brain circuit function and its dysregulation is associated with several neurodevelopmental disorders. A defect in the dendritic growth and elaboration of motor neocortical pyramidal neurons in neonates lacking neuregulin-4 (NRG4) has previously been reported. In this study, we investigated whether the loss of NRG4 causes further morphologic defects that are specific to these neurons. We analyzed the soma size of pyramidal neurons of layer (L)2/3 and L5 of the motor cortex and a subpopulation of multipolar interneurons in this neocortical region in Nrg4+/+ and Nrg4−/− mice. There were significant decreases in pyramidal neuron soma size in Nrg4−/− mice compared with Nrg4+/+ littermates at all stages studied [postnatal day (P)10, P30, and P60]. The reduction was especially marked at P10 and in L5 pyramidal neurons. Soma size was not significantly different for multipolar interneurons at any age. This in vivo phenotype was replicated in pyramidal neurons cultured from Nrg4−/− mice and was rescued by NRG treatment. Analysis of a public single-cell RNA sequencing repository revealed discrete Nrg4 and Erbb4 expression in subpopulations of L5 pyramidal neurons, suggesting that the observed defects were due in part to loss of autocrine Nrg4/ErbB4 signaling. The pyramidal phenotype in the motor cortex of Nrg4−/− mice was associated with a lack of Rotarod test improvement in P60 mice, suggesting that absence of NRG4 causes alterations in motor performance.

Highlights

Neuregulins are signaling proteins that are abundantly expressed in the nervous system where they are required for neuronal development and brain function
Defining the morphologic defects caused by altered NRG4/ErbB4 signaling and their functional consequences aids in our understanding of the crucial mechanisms required for normal cortical development and function in the adulthood
We analyzed the cell soma of neocortical pyramidal and multipolar interneurons of Nrg41/1 and Nrg4À/À mice motor cortex at different stages to identify whether the loss of NRG4 affects soma size, and whether this effect was general or specific to certain populations of neurons

Summary

Significance Statement

Neuregulins are growth factors that are abundantly expressed in the nervous system where they regulate a plethora of processes essential for normal nervous system development and function in adulthood. Dysregulation of neuregulin signaling has been implicated in neurodevelopmental disorders, characterizing the particular functions of members of this family of proteins is highly relevant for understanding how such disorders emerge. This study shows that neuregulin-4 (NRG4) is required to maintain motor cortex pyramidal neuron soma size, and that altered pyramidal neuronal morphology is associated with motor defects in mice

Introduction

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