Modification of microglia function protects from lesion-induced neuronal alterations and promotes sprouting in the hippocampus.

Primary neuronal destruction in the central nervous system triggers rapid changes in glial morphology and function, after which activated glial cells contribute to secondary neuronal changes. Here we show that, after entorhinal cortex lesion, activation of microglia, but not other glial cells, leads to massive secondary dendritic changes of deafferentiated hippocampal neurons. Blocking of microglial activation in vivo reduced this secondary neuronal damage and enhanced regenerative axonal sprouting. In contrast, abolishing astrocytes or oligodendroglia did not result in specific neuronal changes. Furthermore, primary damage leads to an interleukin 1beta up-regulation, which is attenuated by the immuno-modulator transforming growth factor beta1, whereas tumor necrosis factor alpha is not affected. Modification of microglial activity following denervation of the hippocampus protects neurons from secondary dendritic alterations and therefore enables their reinnervation. These data render activated microglia a putative therapeutic target during the course of axonal degeneration.