Microglial contribution to the pathology of neurodevelopmental disorders in humans

Abstract

Microglia are the brain’s resident macrophages, which guide various developmental processes crucial for brain maturation, activity, and plasticity. Microglial progenitors enter the telencephalic wall by the 4th postconceptional week and colonise the fetal brain in a manner that spatiotemporally tracks key neurodevelopmental processes in humans. However, much of what we know about how microglia shape neurodevelopment comes from rodent studies. Multiple differences exist between human and rodent microglia warranting further focus on the human condition, particularly as microglia are emerging as critically involved in the pathological signature of various cognitive and neurodevelopmental disorders. In this article, we review the evidence supporting microglial involvement in basic neurodevelopmental processes by focusing on the human species. We next concur on the neuropathological evidence demonstrating whether and how microglia contribute to the aetiology of two neurodevelopmental disorders: autism spectrum conditions and schizophrenia. Next, we highlight how recent technologies have revolutionised our understanding of microglial biology with a focus on how these tools can help us elucidate at unprecedented resolution the links between microglia and neurodevelopmental disorders. We conclude by reviewing which current treatment approaches have shown most promise towards targeting microglia in neurodevelopmental disorders and suggest novel avenues for future consideration.

Human‐specific insights into candidate genes and boosted discoveries of novel loci illuminate roles of neuroglia in reading disorders

“…For the same reasons, we argue that the neuronal migration hypothesis of RD, previously criticized for lack of robust evidence from either rodent models or human studies, 7 should not be dismissed but instead deserve further investigation that may benefit from the most updated methods to characterize roles of neuroglia in the early development of RD. Our argument is further supported by previous and our current findings that (a) rodent models are useful but not sufficient for human specific problems 53 so cannot be used to dismiss the hypothesis regardless; (b) human microglia has confirmed roles in regulating neuronal migration 51 , 52 , 54 and neuronal migration is considered as a risk factor for autism 55 ; (c) RD is associated with Semaphorins family genes (Figure 2 ) and with gene expression in oligodendrocytes and/or oligodendrocyte precursor cells (Table 2 , Figures 1 , 2 , 3 ), while the class 3 Semaphorins (i.e., SEMA3A , SEMA3C , SEMA3F ) could inhibit the migration of oligodendrocyte precursor cells from the ventricular zones of the brain to the central nervous system 33 and differentiation into mature oligodendrocytes that are essential to form the myelin sheath for efficient transmission of the nervous impulse. 49 …”

Increased NLRP1 mRNA and Protein Expression Suggests Inflammasome Activation in the Dorsolateral Prefrontal and Medial Orbitofrontal Cortex in Schizophrenia

“…Inside the brain, the majority of immune actions are conducted by microglia, as they control innate immune responses and survey the brain parenchyma [ 68 ]. During brain development, microglia play essential roles by regulating cell and synapse numbers, eliminating excess immature synaptic connections, and producing mediators whose profiles vary based on the microglia’s activation state, consequently influencing different neurodevelopmental processes [ 69 , 70 , 71 ]. The mechanisms to explain the involvement of immune system, including microglia, in the pathogenesis of SZ include changes in the developing fetal brain due to prenatal infection and MIA [ 35 , 40 , 72 , 73 , 74 , 75 ].…”

Metabolic dynamics in astrocytes and microglia during post-natal development and their implications for autism spectrum disorders

“…However, the underlying biological mechanisms remain largely unclear. A growing body of evidence suggests that dysregulated glial cells can contribute to many of the neurological symptoms observed in various neurodevelopmental disorders ( Petrelli et al, 2016 , 2023 ; Neniskyte and Gross, 2017 ; Petrelli and Bezzi, 2018 ; Cresto et al, 2019 ; de Oliveira Figueiredo et al, 2022a , b ; Ferrucci et al, 2023 ; Matuleviciute et al, 2023 ; Xiong et al, 2023 ). For instance, while genes implicated in ASDs were initially thought to be exclusively expressed in neurons, recent findings show their expression in astrocytes and microglial cells as well, suggesting a potential role for these cells in the development of these disorders ( McGann et al, 2012 ; Petrelli et al, 2016 ; Petrelli and Bezzi, 2018 ; de Oliveira Figueiredo et al, 2022b ; Ferrucci et al, 2023 ).…”