Mechanisms of microglia-mediated neuronal damage and functional impairment
Microglia-mediated neuronal damage and dysfunction
Recent data have pointed to a central role of glial cells for physiological and pathological function of neurons. Microglial cells constitute a fascinating subpopulation of nonneuronal cells that are present in the CNS at early stages in development. Microglia become activated in a plethora of brain disorders, and are capable of releasing a large number of chemokines, cytokines, and other neuroactive substances such as NO or TNFα. Furthermore, recent evidence indicates that microglial function is modulated by neuronal activity. These lines of evidence suggest that microglia are uniquely positioned to signal to neurons, both in normal neuronal function and in brain pathology. The specific signaling pathways are, however, largely unknown.
In the present project, we will examine the role of microglial signals in the modulation of functional properties of neurons, as well as neuronal susceptibility to cell death. To this end, we will use a controlled in vitro slice culture approach which allows selective depletion of endogenous microglia. We will then introduce genetically modified, fluorescently labeled populations of microglia into microglia-depleted slice cultures, allowing us to monitor spatial and functional interactions between microglia and individual neurons in a highly controlled manner. We will focus on the following key questions: (1) How do microglia modulate synaptic and intrinsic neuronal properties? (2) Do microglia affect axonal ntegrity and transport? (3) Do microglia affect neuronal vulnerability to excitotoxic cell death?
We expect that these data will provide novel insights into physiological and pathophysiological microglia-to-neuronal signaling potentially important for the development of novel treatment concepts for neurodegenerative disorders.