Inflammation is a common etiological factor in the pathogenesis of diverse neurological diseases; however, mechanisms by which inflammation causes neural dysfunction are not well understood. We hypothesize that the pro-inflammatory gamma interferon (IFNgamma) contributes to inflammation-associated neuropathology by acting directly on neurons to induce dendrite retraction and synapse loss. This hypothesis is derived from observations that (1) dendritic atrophy and elevated IFNgamma are coincidental in inflammatory reactions caused by viral infection, trauma or ischemia, in chronic inflammatory or viral diseases such as multiple sclerosis or HIV and in neurodegenerative diseases such as Alzheimer's and Parkinson's disease; and (2) dendritic atrophy has been linked to neural dysfunction. We have recently shown that IFNgamma causes dendritic retraction and synaptic loss in cultured peripheral and central neurons in the absence of adverse effects on cell viability or axons. What is not known is whether IFNgamma elicits the same response in vivo, and if IFNgamma generated by peripheral inflammatory events can initiate dystrophic signals that are propagated back to the soma. The significance of the latter is suggested by observations that many neuropathological inflammatory lesions are largely restricted to white matter or target tissues. Using neurons of the superior cervical ganglion (SCG) as a model system, we will address the following specific aims: 1) Determine if systemic administration of lFNgamma is sufficient to cause dendrite retraction and synapse loss in vivo; 2) Assess whether IFNgamma signaling from distal axons is sufficient to cause dendritic retraction in neurons grown in compartmented chambers; and 3) Determine if peripheral inflammation causes dendritic retraction in vivo and if IFNgamma is necessary for this effect.
Aim 3 will be accomplished by quantifying dendritic arborization in SCG neurons that innervate airways in wildtype, IFNgamma-/- and IFNgamma Ralpha -/- mice following airway infection with Sendai parainfluenza virus. SCG neurons that project to airways will be identified by retrograde labeling with Fast Blue, and dendritic arbors will be visualized using DiI labeling. Major histocompatibility complex-I and nitric oxide synthase expression will be monitored in SCG as biomarkers of exposure to pharmacologically active concentrations of IFNgamma. These studies will provide significant insights regarding the effect of pro-inflammatory cytokines on neural circuitry, and identify a novel mechanism for conveying information about peripheral injury or inflammation to distal brain loci.
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