Regulators of dendritic growth in rat sympathetic neurons in vivo
Gonsiorek, Eugene A, Jr
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Dendrites are the primary site of synapse formation within rat postganglionic sympathetic neurons and are regulated by trophic interactions with the targets, in which they innervate. However, the mechanisms by which trophic factors regulate dendritic growth are not completely understood. We demonstrate that bone morphogenetic proteins (BMPs) act as target derived trophic factors in the induction of dendritic growth in sympathetic neurons. BMPs are expressed in the targets of the sympathetic nervous system including the iris, submandibular gland, and the kidney during a period of rapid dendritic growth in vivo. Furthermore, BMPs are necessary for maintenance of the dendritic arbor since decreasing levels of BMPs in vitro and in vivo leads to dendritic retraction in the sympathetic neurons. Previous studies have demonstrated the proinflammatory cytokine interferon-γ is able to inhibit BMP-induced dendritic growth in vitro. We demonstrate that γ-interferon (IFNγ), at levels consistent with those reported during acute or chronic neuroinflammatory states, causes dendrite retraction and synapse loss in sympathetic neurons in vivo. IFNγ-induced loss of synaptic input occurs in the absence of altered neuronal cell viability or decreased trophic interactions between SCG neurons and their target tissues. Decreased synaptic connectivity in the SCG is coincident with impaired ganglionic neurotransmission as evidenced by an attenuation of the baroreflex in animals treated with IFNγ. Based on these observations we propose a novel mechanism underlying the pathogenesis of neuroinflammatory diseases in which IFNγ-induced selective retraction of dendrites leads to decreased neuronal excitability. Statins, a class of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are widely used in the primary and secondary prevention of coronary artery disease. However, the effects of statins are not limited to the cardiovascular benefits resulting from decreased serum cholesterol levels. We demonstrate that statins inhibit BMP-induced dendritic outgrowth in rat sympathetic neurons in vitro and in vivo. However, these effects of statins are not mediated through a cholesterol synthesis pathway, but through the generation of isoprenoids. We propose that statins inhibit BMP-induced dendritic growth through a RhoA mediated pathway.