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 brain impairment in 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 brain and how 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, 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.

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

“…Moreover, in an independent cohort of animals, we revealed that MIA-induced maternal hypothermia, which correlated with the maternal IL-6 response to poly(I:C), did not predict the behavioral outcomes in the adult offspring. The stronger contribution of within-litter variability observed here is consistent with the findings from a recent study using the poly(I:C)-based MIA model in mice, which revealed larger within-litter than between-litter variability in the context of MIA and disruption of cortical interneuron development [60]. Hence, in addition to between-litter variability [6], factors pertaining to within-litter variability should be considered in MIA models that are implemented in litterbearing mammals such as mice.…”

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

“…However, in this injury model, there were numerous changes in gene expression for synaptic and neurotransmission related genes ( 141 ). 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. In the inflammatory injury models just described, behavioral dysfunction has been reported, including reduced social interaction ( 143 ), short and long-term memory deficits ( 46 , 52 ), attention-shifting deficits, and anxiety-like behavior ( 142 ). These behaviors are commonly found in preterm infants, as described above, and in other NDDs, thus supporting the face validity of these models.…”

Selective vulnerability of supragranular layer neurons in schizophrenia

“…Another conceptual finding in our work is that only some neuronal subtypes of the same family exhibit schizophrenia-associated changes, but not the whole family. For instance, PV interneuron family had been proposed to be impaired in schizophrenia before ( 5, 25, 26 ), and here we show that only supragranular-enriched PVALB_SST and PVALB_CRH subtypes, but not the largest of PVALB subtypes, PVALB_MEPE, have extensive schizophrenia-associated transcriptomic changes. Same holds true for SST, where supragranular-enriched SST_CALB1 subtype showed by far the largest schizophrenia-associated effect compared to other SST subtypes, VIP (e.g.…”

“…Parvalbumin expressing (PV+) interneurons (family PVALB) were also among those with the largest transcriptomic and compositional changes in our schizophrenia snRNA-seq data. Importantly, extensive data in animal models and patients establish a major role of PV+ interneurons in schizophrenia-related cognitive abnormalities ( 5, 25, 26 ). We, therefore, analyzed the density of PV+ interneurons in the same cohort of DLPFC samples.…”