Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain.

Microglia actively survey the brain microenvironment and play essential roles in sculpting synaptic connections during brain development. While microglial functions in the adult brain are less clear, activated microglia can closely appose neuronal cell bodies and displace axosomatic presynaptic terminals. Microglia-mediated stripping of presynaptic terminals is considered neuroprotective, but the cellular and molecular mechanisms are poorly defined. Using 3D electron microscopy, we demonstrate that activated microglia displace inhibitory presynaptic terminals from cortical neurons in adult mice. Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band. Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury. These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.

Observations on the brain vasculature in multiple sclerosis: A historical perspective.

OBJECTIVES: To review the literature on vascular aspects of multiple sclerosis (MS) specifically pathological observations of the perivenular distribution of MS lesions and venous pathology in MS. METHODS: Comprehensive literature search from 2012 back to 1839. RESULTS: One hundred and thirty two papers from 1839 to 2012 were included in this study. Multiple authors observed central venules in MS lesions as a feature of MS with the first specific mention by Rindfleisch in 1863. Recent high field strength MRI has reintroduced the perivenular distribution of MS lesions to a new generation, and has suggested that there is disease specificity to this distribution. In addition Putnam and others in the 1930s hypothesized that venous disease was causative for MS. Treatments based on these observations have included anticoagulation, hyperbaric oxygen therapy, and recently endovascular venous procedures. The significance of these findings in terms of MS pathogenesis has been debated over the same period of time. CONCLUSIONS: While the controversy over venous disease in MS is new, the observation of perivenular MS plaques and venous theories about MS pathogenesis are as old as the history of MS research.