Glial Control of Synapse Number in Healthy and Diseased Brain

Abstract

Glial cells are emerging as crucial players that mediate development and homeostasis of the central nervous system (CNS). In particular, glial cells are closely associated with synapses, and control synapse formation, function, plasticity, and elimination during the stages of development and adulthood. Importantly, it is now increasingly evident that abnormal glial function can be an active inducer of the initiation and progression of various neurodegenerative diseases. Here, we discuss recent developments on the physiological roles of glial cells in the brain, and propose that synapse loss, which is a common characteristic of several neurodegenerative diseases, can be initiated by mis-regulation of normal glial function.

Keywords: Alzheimer’s disease; astrocytes; microglia; neurodegenerative diseases; synapse loss.

Figure 1

Mis-regulation of glial function can lead to synapse loss in neurodegenerative diseases. (A) Astrocytes and microglia release a number of synaptogenic factors [for example, thrombospondins (TSPs), Hevin/SPARC, Glypican 4/6, Chrdl1 from astrocytes, and brain-derived neurotrophicfactor (BDNF) and interleukin 10 (IL10) from microglia], regulating synapse formation. Astrocytes can mediate synapse pruning through MEGF10, MERTK phagocytic pathways whereas microglia contribute to synapse elimination through complement cascades [C1q, C3, and complement receptor 3 (CR3)]. Astrocytes also can regulate microglia-mediated synapse elimination by secreting transforming growth factor beta (TGFβ) and IL33. (B) In neurodegenerative diseases, reactive astrocytes and microglia are found around protein aggregates [such as amyloid β (Aβ) plaques, α-synuclein aggregates] and mediate synapse loss through various mechanisms. Reactive astrocytes may be induced by cytokines (IL-1α, TNF, and C1q) secreted from reactive microglia in pathological conditions, and produce neurotoxic factors that kill synapses and neurons. In addition, reactive astrocytes in Alzheimer’s disease (AD) show increased expression of glutamate transporter-1 (GLT-1), increased activity of transient receptor potential A1 (TRPA1) channels, and increased release of γ-aminobutyric acid (GABA), leading to aberrant neuronal excitability and synaptic function. Similar to astrocytes, reactive microglia can participate in neuronal damage and synapse loss through inflammatory signaling [such as TNF, IL-1β, and reactive oxygen species (ROS)]. Microglia mediate aberrant synapse loss in AD brains through complement mediators (especially C1q and C3) and triggering receptor expressedon myeloid cells 2 (TREM2).