Paramo Blanca, Wyatt Sean, Davies Alun M
School of Biosciences, Cardiff University, Cardiff, UK.
J Neuropathol Exp Neurol. 2019 Aug 1;78(8):725-734. doi: 10.1093/jnen/nlz046.
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.
中等棘状神经元（MSNs）构成了纹状体中绝大多数的神经元。这些广泛连接的神经元丰富的树突变化与多种神经疾病相关，且由多种消遣性和药用药物引起。然而，我们对这一具有临床重要性的神经元群体树突生长和发育的生理调节因子了解甚少。在此，我们发现，与野生型（Nrg4+/+）同窝小鼠相比，在神经调节蛋白-4基因（Nrg4-/-）中具有纯合无效突变的新生小鼠，其MSN树突明显更小且分支更少。Nrg4-/-小鼠在新生儿期和成年期的MSN树突棘数量也显著减少。在Nrg4-/-新生儿中观察到的MSNs惊人的树突发育不良表型在从Nrg4-/-胚胎培养的MSNs中也得到了重现，并且可被可溶性重组神经调节蛋白-4完全挽救。从野生型小鼠培养的MSNs共表达NRG4及其受体ErbB4。我们的研究结果表明，NRG4是纹状体中树突生长、分支和棘形成的一种主要的新型调节因子，并表明它通过自分泌/旁分泌机制发挥作用。
