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.
Highlights
The mammalian neocortex contains two major classes of neurons, projection and local circuit neurons: projection neurons which contain the excitatory neurotransmitter glutamate, and local circuit neurons which are mainlyMarguet et al acta neuropathol commun (2020) 8:208 have reported that contrary to rodents, a proportion of INs in humans could arise from the dorsal telencephalon [24, 32, 44, 69]
The main hallmarks of Foetal Alcohol Spectrum disorder (FASD) interneuronopathy consisted in a delayed generation of γ-aminobutiric acid (GABA) INs expressing calretinin which started from 24 Weeks’ gestation (WG) instead of 18 WG and resulted in an inadequate number of INs, i.e., insufficient in the cortical plate until birth, in excess after birth, as well as in a failure to integrate themselves at their appropriate location within the different layers according to an inside-out pattern
This study provides further evidence that alcohol affects the GABAergic system in humans from early foetal life by impacting on critical stages of brain development and inducing an interneuronopathy
Summary
The mammalian neocortex contains two major classes of neurons, projection and local circuit neurons: projection neurons which contain the excitatory neurotransmitter glutamate, and local circuit neurons which are mainlyMarguet et al acta neuropathol commun (2020) 8:208 have reported that contrary to rodents, a proportion of INs in humans could arise from the dorsal telencephalon [24, 32, 44, 69]. It is well admitted that the majority of INs in primates including humans originate in the ganglionic eminences (GE) [2, 21, 36]. GABAergic IN specification within the GE is linked to the expression of transcription factors encoded by a set of regulatory genes such as Dlx (Distal less homeobox gene), Dlx, Ascl (Achaete-scute family bHLH transcription factor 1) formerly known as Mash, Gsx and Gsx (GeneticScreened Homeobox 1 and 2) [34, 61]. Two lineages of neocortical GABAergic INs exist. The first expresses Dlx1/2 transcription factors, and represents 65% of neocortical GABAergic neurons, originating from Ascl expressing progenitors. The second lineage, which expresses Dlx1/2 but not Ascl, forms around 35% of GABAergic INs [3, 45]. Dlx1/2, Nkx2.1, Lhx, Lhx and ARX participate in the control of GABAergic IN production and migration [16]
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