Microglia Modulate Wiring of the Embryonic Forebrain

Abstract

Dysfunction of microglia, the tissue macrophages of the brain, has been associated with the etiology of several neuropsychiatric disorders. Consistently, microglia have been shown to regulate neurogenesis and synaptic maturation at perinatal and postnatal stages. However, microglia invade the brain during mid-embryogenesis and thus could play an earlier prenatal role. Here, we show that embryonic microglia, which display a transiently uneven distribution, regulate the wiring of forebrain circuits. Using multiple mouse models, including cell-depletion approaches and cx3cr1(-/-), CR3(-/-), and DAP12(-/-) mutants, we find that perturbing microglial activity affects the outgrowth of dopaminergic axons in the forebrain and the laminar positioning of subsets of neocortical interneurons. Since defects in both dopamine innervation and cortical networks have been linked to neuropsychiatric diseases, our study provides insights into how microglial dysfunction can impact forebrain connectivity and reveals roles for immune cells during normal assembly of brain circuits.

Serotonin Modulates Developmental Microglia via 5-HT2B Receptors: Potential Implication during Synaptic Refinement of Retinogeniculate Projections

“…3A). With age, the density of microglia inside the dLGN gradually increases: it almost doubles between P4 and P6 (92.9±19.9 and 161.6±27.4 microglia per mm 2 , respectively), to reach a 4-fold increase in adult animals (358.0 ±50.1 microglia per mm 2 ) (Fig. 3B).…”

“…Recent evidence indicates that brain resident macrophages, microglial cells, are essential for the proper wiring of neuronal networks at postnatal periods 1,2 . The critical process of developmental elimination of inappropriate synapses involves the phagocytic activity of microglia 3,4 , however, the influence of microglial cells on synapse development most likely extends beyond their phagocytic capabilities.…”

Emerging roles of gut microbiota and the immune system in the development of the enteric nervous system

“…More recent studies have identified a role for microglia in synaptogenesis and synaptic transmission, indicating that these cells contribute to the formation and maturation of neural circuits and the pathogenesis of neurodevelopmental disorders such as ASD and schizophrenia. Remarkably, microglial cell activity can influence neural network formation not only during perinatal and postnatal stages, but also during embryogenesis (133). Macrophages are present throughout the gut, including the muscularis externa (muscularis macrophages), where they come into close contact with components of the ENS (134,135).…”

Role of microglia in fungal infections of the central nervous system

“…40,41 These findings were later validated by showing that microglia's transcriptomic activity is unambiguously different to those of peripheral monocytederived macrophages, regardless of their anatomical origin. 18 Likewise, numerous studies have demonstrated microglia's own biological identity including the regulation of synaptic pruning and plasticity, [42][43][44] the spatial distribution of axonal projections, 45,46 and neuronal homeostasis and survival. 47,48 Alternatively, a current hypothesis proposes that microglial reactivity may be stimulated by damaged neurons with deficient signaling, the presence of circulatory plasma molecules in the CNS due to the BBB disruption, and peripheral leukocyte signaling mediated by cytokines after interactions with microbes or their antigens.…”