The role of glial cells in synapse elimination

Abstract

Excessive synapses generated during early development are eliminated extensively to form functionally mature neural circuits. Synapses in juvenile and mature brains are highly dynamic, and undergo remodeling processes through constant formation and elimination of dendritic spines. Although neural activity has been implicated in initiating the synapse elimination process cell-autonomously, the cellular and molecular mechanisms that transduce changes in correlated neural activity into structural changes in synapses are largely unknown. Recently, however, new findings provide evidence that in different species, glial cells, non-neuronal cell types in the nervous system are crucial in eliminating neural debris and unwanted synapses through phagocytosis. Glial cells not only clear fragmented axons and synaptic debris produced during synapse elimination, but also engulf unwanted synapses thereby actively promoting synapse elimination non-cell autonomously. These new findings support the important role of glial cells in the formation and maintenance of functional neural circuits in development as well as in adult stages and neurodegenerative diseases.

Figure 1. Schematic drawing illustrating input elimination and individual synapse elimination

(a) Input elimination at the mammalian NMJ. Axons from motor neurons form connections with muscle fibers. Initially, each NMJ has multiple inputs from two or more motor neurons. Through activity-dependent intercellular competition, the “loser” axon retracts and is eventually eliminated, leaving a one-to-one match between each motor input and NMJ. (b) Individual synapse elimination in the brain. During learning and memory formation, new spines (red arrowheads) form rapidly (light red circles) and are stabilized, whereas synapses that existed previously (light black circles) are preferentially eliminated (black arrowheads).

Figure 2. Roles of glial cells in synapse elimination

(a) At the Drosophila NMJ, glial cells clear synaptic debris produced during synaptic growth [18**]. A single arbor from the motor neuron (red) innervates a muscle fiber (light blue) and forms synaptic boutons (dark blue). In response to changes in growth and/or activity, the addition of new synaptic connections with the muscle cell involves significant production of presynaptic debris and ghost boutons. The presynaptic debris and ghost boutons are engulfed and eliminated by glial (green) and muscle cells (light blue), respectively. Knocking down Draper or dCed-6 function in glia results in the accumulation of presynaptic debris, whereas blocking muscle-mediated phagocytosis causes the accumulation of ghost boutons. Disruption of clearing either one of the neural debris is sufficient to interfere with proper formation of synaptic boutons and lead to severely compromised synaptic growth. (modified from Ref. [18]) (b) In the mammalian brain, microglia (red) actively promote synapse disassembly (arrowheads) [35, 46**, 49**, 51*]. In the normal brain, microglial processes localize at small and growing dendritic spines, which are eliminated eventually (black arrowheads). Inclusions derived from pre- and postsynaptic elements (green in light yellow circles) are found inside of microglial processes. Studies have suggested that mice with defects in the complement cascade [35, 51*]or fractalkine signaling [49**] show the increased total synaptic density due to the failure of microglial-mediated synapse elimination.