Prenatal alcohol exposure is a leading cause of interneuronopathy in humans

Abstract

Alcohol affects multiple neurotransmitter systems, notably the GABAergic system and has been recognised for a long time as particularly damaging during critical stages of brain development. Nevertheless, data from the literature are most often derived from animal or in vitro models. In order to study the production, migration and cortical density disturbances of GABAergic interneurons upon prenatal alcohol exposure, we performed immunohistochemical studies by means of the proliferation marker Ki67, GABA and calretinin antibodies in the frontal cortical plate of 17 foetal and infant brains antenatally exposed to alcohol, aged 15 weeks’ gestation to 22 postnatal months and in the ganglionic eminences and the subventricular zone of the dorsal telencephalon until their regression, i.e., 34 weeks’ gestation. Results were compared with those obtained in 17 control brains aged 14 weeks of gestation to 35 postnatal months. We also focused on interneuron vascular migration along the cortical microvessels by confocal microscopy with double immunolabellings using Glut1, GABA and calretinin. Semi-quantitative and quantitative analyses of GABAergic and calretininergic interneuron density allowed us to identify an insufficient and delayed production of GABAergic interneurons in the ganglionic eminences during the two first trimesters of the pregnancy and a delayed incorporation into the laminar structures of the frontal cortex. Moreover, a mispositioning of GABAergic and calretininergic interneurons persisted throughout the foetal life, these cells being located in the deep layers instead of the superficial layers II and III. Moreover, vascular migration of calretininergic interneurons within the cortical plate was impaired, as reflected by low numbers of interneurons observed close to the cortical perforating vessel walls that may in part explain their abnormal intracortical distribution. Our results are globally concordant with those previously obtained in mouse models, in which alcohol has been shown to induce an interneuronopathy by affecting interneuron density and positioning within the cortical plate, and which could account for the neurological disabilities observed in children with foetal alcohol disorder spectrum.

Cell-type and fetal-sex-specific targets of prenatal alcohol exposure in developing mouse cerebral cortex

“…Overall, the transcriptome of interneuron clusters that were present in this region of the developing cerebral cortex were among the least affected by alcohol exposure, in contrast to significant effects on interneurons observed in other PAE models (Marguet et al, 2020;Skorput et al, 2015). However, one interneuron cluster, cluster #11, was specifically affected by PAE in both males and females, but in opposite directions.…”

Oligodendrocyte lineage is severely affected in human alcohol-exposed foetuses

“…Since oligodendrocyte development and myelin are a target of alcohol, the disruption of oligodendrocyte differentiation and of myelination process is very likely responsible for inadequate establishment of neuronal networks and inefficient conduction of neuronal signals. Disruption of oligodendrocyte generation and differentiation, together with GABA interneuronopathy that we previously identified [ 28 ], most likely contribute to developmental encephalopathy and subsequent life-long neuro-behavioural disabilities.…”

“…As previously reported [ 28 ], the brains used in this study belong to the collection which has been declared to the French Ministry of Health (collection number DC-2015-2468, cession number AC-2015-2467, located in A. Laquerrière’s Pathology Laboratory, Rouen University hospital). In each case, the parents gave their informed written consent for neuropathological studies.…”

Divergent and overlapping hippocampal and cerebellar transcriptome responses following developmental ethanol exposure during the secondary neurogenic period

“…Numerous animal models have shown that interneurons are sensitive to EtOH in various brain regions, including the striatum, medial prefrontal cortex, cerebral cortex, orbitofrontal cortex, and hippocampus (Bird et al, 2018; De Giorgio et al, 2012; Hamilton et al, 2017; Kenton et al, 2020; Madden et al, 2020; Sadrian et al, 2014; Saito et al, 2018; Smiley et al, 2015). Consequently, developmental EtOH exposure has previously been characterized as resulting in “interneuronopathy” (Bird et al, 2018; Madden et al, 2020; Marguet et al, 2020; Skorput et al, 2015; Smiley et al, 2015). However, the effects of EtOH exposure are not always inhibitory.…”