The expression of interferon gamma (IFNgamma) increases after neural injury, and it is sustained in chronic inflammatory conditions such as multiple sclerosis and infection with human immunodeficiency virus. To understand how exposure to this proinflammatory cytokine might affect neural function, we examined its effects on cultures of neurons derived from the central and peripheral nervous systems. IFNgamma inhibits initial dendritic outgrowth in cultures of embryonic rat sympathetic and hippocampal neurons, and this inhibitory effect on process growth is associated with a decrease in the rate of synapse formation. In addition, in older cultures of sympathetic neurons, IFNgamma also selectively induces retraction of existing dendrites, ultimately leading to an 88% decrease in the size of the arbor. Dendritic retraction induced by IFNgamma represents a specific cellular response because it occurs without affecting axonal outgrowth or cell survival, and it is not observed with tumor necrosis factor alpha or other inflammatory cytokines. IFNgamma-induced dendritic retraction is associated with the phosphorylation and nuclear translocation of signal transducer and activator of transcription 1 (STAT1), and expression of a dominant-negative STAT1 construct attenuates the inhibitory effect of IFNgamma. Moreover, retrograde dendritic retraction is observed when distal axons are selectively exposed to IFNgamma. These data imply that IFNgamma-mediated STAT1 activation induces both dendritic atrophy and synaptic loss and that this occurs both at the sites of IFNgamma release and at remote loci. Regressive actions of IFNgamma on dendrites may contribute to the neuropathology of inflammatory diseases.

Dendritic growth in cultured sympathetic neurons requires specific trophic interactions. Previous studies have demonstrated that either coculture with glia or exposure to recombinant bone morphogenetic proteins (BMPs) is both necessary and sufficient to induce dendrite formation. These observations led us to test the hypothesis that BMPs mediate glial-induced dendritic growth. In situ hybridization and immunocytochemical studies indicate that the spatiotemporal expression of BMP5, -6, and -7 in rat superior cervical ganglia (SCG) is consistent with their proposed role in dendritogenesis. In vitro, both SCG glia and neurons were found to express BMP mRNA and protein when grown in the presence or absence of the other cell type. However, addition of ganglionic glia to cultured sympathetic neurons causes a marked increase in BMP proteins coincident with a significant decrease in follistatin and noggin. Functional assays indicate that glial-induced dendritic growth is significantly reduced by BMP7 antibodies and completely inhibited by exogenous noggin and follistatin. These data suggest that glia influence the rapid perinatal expansion of the dendritic arbor in sympathetic neurons by increasing BMP activity via modulation of the balance between BMPs and their antagonists.

Background: BMP-5 is expressed in the nervous system throughout development and into adulthood. However its effects on neural tissues are not well defined. BMP-5 is a member of the 60A subgroup of BMPs, other members of which have been shown to stimulate dendritic growth in central and peripheral neurons. We therefore examined the possibility that BMP-5 similarly enhances dendritic growth in cultured sympathetic neurons.