Astrocytes, microglia, and the locus coeruleus: A histological analysis of the effects of norepinephrine depletion on glial biology in the mouse brain

Abstract

In contrast to the historical view that glial cells function primarily as homeostatic regulators that support neuronal function, a great deal of evidence has now emerged that glia actively participate in every major aspect of brain development, function and disease. Despite these exciting data, however, the cellular mechanisms underlying both the well-established and emerging functions of glial cells remain poorly understood. In this study, we sought to further characterize the role of glia in brain function by testing how astrocyte and microglial morphology and protein expression are regulated by the neuromodulator norepinephrine (NE). To do so, several brain regions heavily innervated by noradrenergic fibers projecting from the locus coeruleus (LC) were examined for changes in protein expression and cell morphology in mice injected with the noradrenergic axonterminal specific neurotoxin DSP-4. Our experiments demonstrated that astrocyte cell body size and microglial cell number increase in the medial prefrontal cortex (mPFC) and the CA1 region of the hippocampus in response to DSP-4 injection. We further showed that DSP-4 injection increases the immunofluorescent optical intensity of glial fibrillary acidic protein (GFAP) in the mPFC and CA1 as well as the optical intensity of Iba1 in the mPFC. Together, our findings support a role for NE in regulating astrocyte and microglial biology in ways potentially important for neuroplasticity and behavior. Furthermore, our results question the validity of using lesion studies to characterize neuronal function without considering their effects on glial cells.