Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner

Abstract

Severe infections during pregnancy are one of the major risk factors for cognitive impairment in the offspring. It has been suggested that maternal inflammation leads to dysfunction of cortical GABAergic interneurons that in turn underlies cognitive impairment of the affected offspring. However, the evidence comes largely from studies of adult or mature brains and how the impairment of inhibitory circuits arises upon maternal inflammation is unknown. Here we show that maternal inflammation affects multiple steps of cortical GABAergic interneuron development, i.e., proliferation of precursor cells, migration and positioning of neuroblasts, as well as neuronal maturation. Importantly, the development of distinct subtypes of cortical GABAergic interneurons was discretely impaired as a result of maternal inflammation. This translated into a reduction in cell numbers, redistribution across cortical regions and layers, and changes in morphology and cellular properties. Furthermore, selective vulnerability of GABAergic interneuron subtypes was associated with the stage of brain development. Thus, we propose that maternally derived insults have developmental stage-dependent effects, which contribute to the complex etiology of cognitive impairment in the affected offspring.

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

“…In this same animal model, and similar to data reported in human cases, a specific alteration in interneuron number was identified in the neocortex (42)-a finding supported by a number of other early-life inflammatory exposure models (142,143) and preterm birth models (4). It is likely that the migration and differentiation of these cell populations is affected, though many studies show that injury reduces or repairs in adult mice, following early-life inflammation (42,143). The important advantage of rodent models is the potential for behavioral testing, where aspects of human clinical disease can be recapitulated.…”

Regenerative Therapies to Restore Interneuron Disturbances in Experimental Models of Encephalopathy of Prematurity

“…Consistent with previous studies that showed susceptibility of interneurons to perinatal insults in animal models and post-mortem human tissue, we observed differences in interneuron density following induction of EoP in both our models [ 19 , 20 , 21 , 23 , 24 , 25 , 62 ]. However, the previous published studies generally use single-hit (fetal/postnatal inflammation or hypoxia) models, failing to reflect the multifactorial etiology of EoP [ 19 , 23 , 24 , 25 , 26 , 27 ].…”

Maternal choline and respiratory coronavirus effects on fetal brain development

“…The timing of the effect on viral infection at the beginning of the second trimester on the development of infant behavior is consistent with investigations in human fetal brain. Inhibitory interneurons are being formed in the hippocampus in this gestational window, when they are most vulnerable to maternal inflammation (Vasistha et al, 2019). Fetal development of inhibitory interneuron function, as measured by cerebral evoked potential inhibition in newborns, is associated with the development of infant attention and other self-regulatory behavior as measured with the IBQ-R Regulation dimension (Freedman et al, 2019).…”