Effect of Neuroinflammation on Synaptic Organization and Function in the Developing Brain: Implications for Neurodevelopmental and Neurodegenerative Disorders

Abstract

The brain is a plastic organ where both the intrinsic CNS milieu and extrinsic cues play important roles in shaping and wiring neural connections. The perinatal period constitutes a critical time in central nervous system development with extensive refinement of neural connections, which are highly sensitive to fetal and neonatal compromise, such as inflammatory challenges. Emerging evidence suggests that inflammatory cells in the brain such as microglia and astrocytes are pivotal in regulating synaptic structure and function. In this article, we will review the role of glia cells in synaptic physiology and pathophysiology, including microglia-mediated elimination of synapses. We propose that activation of the immune system dynamically affects synaptic organization and function in the developing brain. We will discuss the role of neuroinflammation in altered synaptic plasticity following perinatal inflammatory challenges and potential implications for neurodevelopmental and neurodegenerative disorders.

Keywords: neurodegenerative diseases; neurodevelopmental disorders; neuroinflammation; preterm infant; synapse formation.

Figure 1

Time line of human brain development in the perinatal period. Developmental time course of neurons (Lenroot and Giedd, ; Budday et al., ; Paredes et al., 2016), synapses (Huttenlocher and Dabholkar, ; Glantz et al., 2007), astrocytes (Roessmann and Gambetti, ; Budday et al., 2015), microglia (Esiri et al., ; Monier et al., 2007), oligodendrocytes (Rakic and Zecevic, ; Yeung et al., 2014), myelination (Tosic et al., ; Yeung et al., 2014), choroid plexus (Dziegielewska et al., 2001) and vasculature (Budday et al., 2015) in the human brain. Major complications during the perinatal period are shown. W1, week 1; M4, month 4; Y1, year 1; EL, elimination.

Figure 2

Hypothesis of how perinatal neuroinflammation can cause abnormal synapse pruning. We hypothesize that neuroinflammation at the time around birth dysregulates synaptic function and/or synaptic pruning that can lead to neurodevelopmental disorders. During normal development, silent (green) synapse terminals are appropriately pruned (phagocytosis) by glia cells (microglia and astrocytes) so that only active healthy (red) synapses remain (left). Complement protein 3 (C3), and C1q tag synapses for elimination by microglia during normal development and transforming growth factor (TGF)-β regulates C1q expression in neurons (Stevens et al., ; Bialas and Stevens, 2013). Astrocyte-mediated synapse pruning is complement-independent and is regulated by MEGF10 and MERTK pathways (Chung et al., 2013). We propose that perinatal neuroinflammation can directly stimulate/inhibit synaptic functions so that pruning rates by glial cells are adjusted and more/less synapses remain. Another possible pathological process is that neuroinflammation will change glia cells to a more pruning-prone phenotype resulting in overpruning so that some active healthy synapses are eliminated and fewer than normal synapses remain (middle) or to a reverse glial phenotype so that too many synapses remain (right).