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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.

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