Reciprocal Interactions Between Microglia and Neurons: From Survival to Neuropathology

Microglia represent a major cellular component of the brain, where they constitute a widely distributed network of immunoprotective cells. During the last decades, it has become clear that the functions traditionally ascribed to microglia, i.e. to dispose of dead cells and debris and to mediate brain inflammatory states, are only a fraction of a much wider repertoire of functions spanning from brain development to aging and neuropathology. The aim of the present survey is to critically discuss some of these functions, focusing in particular on the reciprocal microglia-neuron interactions and on the complex signaling systems subserving them. We consider first some of the functional interactions dealing with invasion, proliferation and migration of microglia as well as with the establishment of the initial blueprint of neural circuits in the developing brain. The signals related to the suppression of immunological properties of microglia by neurons in the healthy brain, and the derangement from this physiological equilibrium in aging and diseases, are then examined. Finally, we make a closer examination of the reciprocal signaling between damaged neurons and microglia and, on these bases, we propose that microglial activation, consequent to neuronal injury, is primarily aimed at neuroprotection. The loss of specific communication between damaged neurons and microglia is viewed as responsible for the turning of microglia to a hyperactivated state, which allows them to escape neuronal control and to give rise to persistent inflammation, resulting in exacerbation of neuropathology. The data surveyed here point at microglial-neuron interactions as the basis of a complex network of signals conveying messages with high information content and regulating the most important aspects of brain function. This network shares similar features with some fundamental principles governing the activity of brain circuits: it is provided with memory and it continuously evolves in relation to the flow of time and information.