Microglial response to degeneration of serotonergic axon terminals

The neurotoxic drug p ‐chloramphetamine (PCA) causes widespread de‐generation offine, 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 micro‐glial 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. © 1994 Wiley‐Liss, Inc.