Microglial response to degeneration of serotonergic axon terminals.
The neurotoxic drug p-chloramphetamine (PCA) causes widespread degeneration of fine, unmyelinated serotonergic (5-HT) axons in the forebrain. PCA toxicity is selective for 5-HT axon terminals; preterminal axons and cell bodies are spared. Degeneration is followed by slowly progressive axonal sprouting and partial reinnervation. PCA is injected subcutaneously; this route of administration avoids mechanical disruption of the blood brain barrier. The present study analyzed the response of microglia and astrocytes in rat brain to selective ablation of 5-HT axons by PCA. Several microglial markers were analyzed with immunocytochemical methods. An increase in the number of microglial processes and in immunoreactive staining was observed with antibodies directed against CR-3, MHC-I, CD4, and rat LCA. The microglial response was maximal 3 weeks after PCA treatment, became less evident 6 weeks after treatment, and by 9 weeks no difference was observed between treated and control rats. No change was detected in MHC-II or the macrophage marker ED1, nor in expression of GFAP by astrocytes. Thus, degeneration of 5-HT axon terminals affects only a subset of the microglial markers examined; in comparison, retrograde reaction to facial nerve transection causes a robust increase in all of these markers and in GFAP. The microglial response to PCA-induced axon loss is slow in onset and small in magnitude. These findings indicate that CNS microglia are activated by degeneration of fine, unmyelinated 5-HT axon terminals; furthermore, sensitive microglial markers can detect a subtle axonal lesion that provokes no detectable increase in GFAP expression by astrocytes.
Wilson
M A
MA
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Molliver
M E
ME
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers; D005154:Facial Nerve / Q000166:cytology; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000276:immunology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D017628:Microglia / Q000502:physiology* / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000187:drug effects / Q000502:physiology*; D017729:Presynaptic Terminals / Q000276:immunology / Q000502:physiology* / Q000648:ultrastructure; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects; D011903:Raphe Nuclei / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000276:immunology / Q000502:physiology*; D010133:p-Chloroamphetamine / Q000494:pharmacology
D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D012701:Serotonin; D010133:p-Chloroamphetamine