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.

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

“…It was shown that microglia of adult rats exposed to E. coli bacteria in the neonatal period had a stronger response to a secondary LPS challenge compared to naïve rats' microglia. [79][80][81] In all, 102 identical DMRs were identified between P4 and P24 for which half preserved their methylation status and the other half shifted to the opposite status. 73 Indeed, the methylation alterations in inflammatory pathways seen in this study could be a key component of a chronic low-level inflammation state, which is being increasingly recognized as central to cognitive decline, neuropsychiatric, and neurodegenerative diseases.…”

The involvement of astrocytes in early‐life adversity induced programming of the brain

“…During week 3 and 4 of postnatal development, astrocytes appear to have a more mature phenotype (Bushong et al, 2004). In humans, the peak of astrogenesis is believed to already start during the last phase of gestation (Menassa & Gomez-Nicola, 2018;Mottahedin et al, 2017; N. Patro, Naik, & Patro, 2015;Semple, Blomgren, Gimlin, Ferriero, & Noble-Haeusslein, 2013) and to last throughout the postnatal period, when the number of GFAP + cells continues to increase in every part of the CNS (Roessmann & Gambetti, 1986). Thus, in both human and rodents, astrogenesis coincides with early sensitive periods rendering astrocytes particularly sensitive to ELA.…”

Maternal immune activation in neurodevelopmental disorders

“…Epidemiological and preclinical studies are beginning to elucidate some of the mechanisms that may be involved: neuroimmune interaction is increasingly implicated in the etiology of neuropsychiatric disorders (Khandaker et al, 2015;M€ uller et al, 2015;Stuart et al, 2015;Garc ıa-Bueno et al, 2016;Leboyer et al, 2016;Mottahedin et al, 2017). Microglia, the resident immune cells of the central nervous system (CNS), are now thought to play roles in normal brain development and maturation, including the refinement of neural circuitry, the promotion of developmental apoptosis, and synaptic pruning (Paolicelli et al, 2011;Wu et al, 2013;Nayak et al, 2014;Mosser et al, 2017).…”