In summary, the recent attention focused on the role of microglia in the healthy brain has elicited several exciting new findings suggesting that microglia play dynamic roles at developing and mature synapses (see Table 1). The interactions between microglia and synapses are dependent upon direct, physical contact as well as signaling via soluble factors. On a functional level, it is now clear that microglia interact with and/or engulf synaptic elements in a manner dependent upon neural activity, mediate synaptic pruning in at least one region of the developing CNS, regulate synapse maturation, and modulate plasticity (LTP and synaptic scaling) and basal transmission in the mature CNS. As a result of these important first studies, several questions have arisen and remain unanswered in the field. First, in the context of the developing CNS, while it is clear that complement-dependent phagocytic signaling is one pathway underlying physical interactions between microglia and remodeling synapses, other, yet to be identified, pathways must also be involved. Second, at this point, data demonstrate that phagocytosis of synaptic elements and pruning are temporally correlated. It remains to be determined whether engulfment of synaptic elements is, indeed, an underlying mechanism of plasticity and an active process by which microglia selectively engulf intact synapses destined for elimination. Furthermore, while current imaging data in the cortex and hippocampus suggest a role for microglia in activity-dependent synaptic remodeling or maturation (Paolicelli et al.,2011; Tremblay et al.,2010), it is still unclear whether microglia are necessary for bona fide synaptic pruning in these other brain regions, and if so, what are the underlying mechanisms? In the context of the mature adult CNS, while several molecular pathways have been identified to contribute to synaptic plasticity and basal transmission in slice and cultured cell preparations, in vivo contributions are still relatively unclear with only a few behavioral correlates. In addition, in the mature CNS, it is unknown whether and how microglia-specific pathways may interact with one another to affect neurotransmission and plasticity and whether many of these molecular pathways have similar or different functions in the context of microglia in the developing brain (Fig. 1, panels A–C).

Table 1. Overview of Synapse-Related Microglia Functions См. в оригинале статьи

Imperative to our understanding of these mysterious cells is the use of in vivo strategies. Microglia are highly reactive cells that respond within minutes to manipulation (Davalos et al.,2005; Hanisch and Kettenmann,2007; Kreutzberg,1996; Nimmerjahn et al.,2005; Ransohoff and Perry,2009). Thus, while in vitro preparations (e.g., isolated cells, acute slice, slice culture, etc.) are important and necessary strategies for dissecting mechanism and function, the physiological relevance and molecular mechanisms identified must be confirmed in vivo. Future in vivo studies using a combinatorial approach of live imaging and molecular biology, including the use of newly derived cre lines (Parkhurst et al.,2011 ), should significantly advance our understanding of the function of microglia at synapses and the molecular mechanisms underlying these interactions. Given that several prevalent psychiatric and developmental disorders (e.g., schizophrenia, OCD, autism, etc.) have recently been linked to deficits in synapse development and/or function, as well as a growing body of evidence suggesting abnormalities in microglia (Derecki et al.,2012; Maezawa and Jin,2010; Monji et al.,2009b; Morgan et al.,2010; Steiner et al.,2008; Vargas et al.,2005; Yang and Lu,2011), understanding functions and molecular pathways underlying microglia-synapse interactions in the healthy brain becomes imperative. This knowledge of molecules and function is important for advancing our understanding of basic biological mechanisms as well as for the promise of developing novel diagnostic and therapeutic strategies associated with CNS disease and injury.