Microglia: an active player in the regulation of synaptic activity

Abstract

Synaptic plasticity is critical for elaboration and adaptation in the developing and developed brain. It is well established that astrocytes play an important role in the maintenance of what has been dubbed "the tripartite synapse". Increasing evidence shows that a fourth cell type, microglia, is critical to this maintenance as well. Microglia are the resident macrophages of the central nervous system (CNS). Because of their well-characterized inflammatory functions, research has primarily focused on their innate immune properties. The role of microglia in the maintenance of synapses in development and in homeostasis is not as well defined. A number of significant findings have shed light on the critical role of microglia at the synapse. It is becoming increasingly clear that microglia play a seminal role in proper synaptic development and elimination.

Figures

Figure 1

Microglia alter the synaptic density of hippocampal neurons. Hippocampal neurons with or without microglia were stained with PSD95 (green), synapsin I (blue), and phalloidin (red) (a). The smaller boxes show magnified images. Arrows depict PSD95+ synapsin 1− puncta. Scale bars: 20 μm (upper panel); 5 μm (lower panel). Quantification of spine numbers (b), PSD95+synapsin 1+ puncta (c), and PSD95+ synapsin 1+ puncta in total PSD95+ puncta (d) in neurons cultured with or without microglia. Values are presented as mean ± SEM and expressed as a percent of the neurons-only control sample (adapted from [28]).

Figure 2

Microglial tPA deficiency preserves the levels of synaptic adhesion molecules. (a) Hippocampal neurons at 19 DIV were cocultured with microglia for 2 days. (b) The western blot analysis of the levels of N-cadherin, pan-γ-protocadherin, and SynCAM-1 in neurons in the absence or presence of microglia from wild-type (WT) or tPAKO(tPA−/−) mice. α-Tubulin was used as a loading control. (c) Quantification was performed using the ImageJ software and normalized against α-tubulin (n = 4). *P < 0.05 compared to neurons alone.

Figure 3

Schematic depicting some of the potential mechanisms through which microglia can affect neuronal activity. Potential interactions between neurons, astrocytes, and microglia at the synapse. The area depicted by the red circle is magnified in inset. Inset: microglial processes in proximity to neuronal synapses can modify neuronal activity via multiple potential pathways. They can secrete proteases to modulate the stability of synaptic adhesion molecules (which in turn influences synaptic transmission) or remove complement-tagged structures. They can release ectosomes that directly interact with the neuronal membranes and initiate signaling cascades. They can also affect directly glutamatergic or GABAergic transmission.