Neuregulin-4 Is Required for the Growth and Elaboration of Striatal Medium Spiny Neuron Dendrites

Medium spiny neurons (MSNs) comprise the vast majority of neurons in the striatum. Changes in the exuberant dendrites of these widely connected neurons are associated with a multitude of neurological conditions and are caused by a variety of recreational and medicinal drugs. However, we have a poor understanding of the physiological regulators of dendrite growth and elaboration of this clinically important population of neurons. Here, we show that MSN dendrites are markedly smaller and less branched in neonatal mice that possess a homozygous null mutation in the neuregulin-4 gene (Nrg4(−)(/)(−)) compared with wild type (Nrg4(+/+)) littermates. Nrg4(−)(/)(−) mice also had a highly significant reduction in MSN dendrite spine number in neonates and adults. The striking stunted dendrite arbor phenotype of MSNs observed in Nrg4(−)(/)(−) neonates was replicated in MSNs cultured from Nrg4(−)(/)(−) embryos and was completely rescued by soluble recombinant neuregulin-4. MSNs cultured from wild type mice coexpressed NRG4 and its receptor ErbB4. Our findings show that NRG4 is a major novel regulator of dendritic growth and arborization and spine formation in the striatum and suggest that it exerts its effects by an autocrine/paracrine mechanism.