The role of microglia in brain maintenance: implications for Rett syndrome

Abstract

The role of microglia in central nervous system pathology has been studied extensively, and more recently, examination of microglia in the healthy brain has yielded important insights into their many functions. It was long assumed that microglia were essentially “quiescent” cells, unless provoked into activation, which was considered a hallmark of disease. More recently, however, it has become increasingly clear that they are extraordinarily dynamic cells, constantly sampling their environment and adjusting to exquisitely delicate stimuli. Along these lines, our lab has identified a new and unexpected role for microglial phagocytosis—or lack thereof—in the pathophysiology of Rett syndrome, a neurodevelopmental disease caused by mutation of the gene encoding methyl-CpG binding protein (MECP)2. Namely, we showed that specific expression of wild-type Mecp2 in myeloid cells of Mecp2-null mice is sufficient to arrest major symptoms associated with this devastating disease. This beneficial effect, however, is abolished if phagocytic activity of microglia is inhibited. Here, we will discuss microglial origins, the role of microglia in brain development and maintenance, and the phenomenon of microglial augmentation by myeloid progenitor cells in the adult brain. Finally, we will address in some detail the beneficial roles of microglia as clinical targets in Rett syndrome and other neurological disorders.

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

“…(ii) Microglial cytokine secretion can affect neural/glial specification, 59 and cytokines such as interleukin-2 (IL-2), whose gene expression was shown to be altered in our analyses, can exert toxic effects on oligodendrocytes and myelin. The consequences of such changes on global myelin genesis are as yet unknown.…”

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

“…The cortex, choroid plexus, and endothelial cells are regions with the highest expression of receptors-the last two are major entry points of systemic IGF1 into the CNS, consistent with the importance of peripheral IGF1 in the maintenance of CNS levels. Nevertheless, the importance of locally synthesized IGF1 in the brain cannot be ruled out, as recent findings show a possible role for environmental enrichment paradigms and active microglia in the production of brain IGF1 (45,46).…”

Dysregulation of Glutamine Transporter SNAT1 in Rett Syndrome Microglia: A Mechanism for Mitochondrial Dysfunction and Neurotoxicity

“…We and others previously showed a role of microglial abnormalities in RTT in mouse models (Maezawa and Jin, 2010;Derecki et al, 2012). Remarkably, MECP2 knock-out (Mecp2Ϫ/y) mice, which manifest human RTT-like symptoms and die at 9 -10 weeks, became almost normal and lived to 1 year after their brains were populated with wild-type myeloid cells/microglia.…”

“…Remarkably, MECP2 knock-out (Mecp2Ϫ/y) mice, which manifest human RTT-like symptoms and die at 9 -10 weeks, became almost normal and lived to 1 year after their brains were populated with wild-type myeloid cells/microglia. They also showed significant phenotypic reversal after genetic reexpression of Mecp2 in myeloid cells (Derecki et al, 2012). Therefore, how MeCP2-deficient microglia (MDM) influence RTT pathology becomes a critical issue.…”

“…Therefore, how MeCP2-deficient microglia (MDM) influence RTT pathology becomes a critical issue. MeCP2 is essential for microglial phagocytotic capability (Derecki et al, 2012) and is involved in fine-tuning of microglial responses to activation signals (Maezawa and Jin, 2010). Moreover, MDM constitutively produce glutamate at levels that could cause smoldering neurotoxicity manifested as pruning of synapses and dendrites (Hutchins and Barger, 1998;Maezawa and Jin, 2010), which could thus contribute to the synaptic/dendritic pathology of RTT.…”