Abstract
Early life stress has profound effects on the development of the central nervous system. We exposed 9-day-old rat pups to a 24 h maternal deprivation (MD) and sacrificed them as young adults (60-day-old), with the aim to study the effects of early stress on forebrain circuitry. We estimated numbers of various immunohistochemically defined interneuron subpopulations in several neocortical regions and in the hippocampus. MD rats showed reduced numbers of parvalbumin-expressing interneurons in the CA1 region of the hippocampus and in the prefrontal cortex, compared with controls. Numbers of reelin-expressing and calretinin-expressing interneurons were also reduced in the CA1 and CA3 hippocampal areas, but unaltered in the neocortex of MD rats. The number of calbinin-expressing interneurons in the neocortex was similar in the MD rats compared with controls. We analyzed cell death in 15-day-old rats after MD and found no difference compared to control rats. Thus, our results more likely reflect the downregulation of markers than the actual loss of interneurons. To investigate synaptic activity in the hippocampus we immunostained for glutamatergic and inhibitory vesicular transporters. The number of inhibitory synapses was decreased in the CA1 and CA3 regions of the hippocampus in MD rats, with the normal number of excitatory synapses. Our results indicate complex, cell type-specific, and region-specific alterations in the inhibitory circuitry induced by maternal deprivation. Such alterations may underlie symptoms of MD at the behavioral level and possibly contribute to mechanisms by which early life stress causes neuropsychiatric disorders, such as schizophrenia.
Highlights
According to the neurodevelopmental theory of schizophrenia, this mental illness represents the end stage of a process that starts long before its clinical presentation and is caused by the combination of early life stress and genetic factors (Kinros et al, 2010; Rapoport et al, 2012; Bora, 2015)
A small (10%), but significant reduction in density of PV+ cells was observed in the prefrontal cortex (49.8 ± 0.86/mm2 vs. 55.2 ± 1.62/mm2 in maternal deprivation (MD) vs. control rats, n = 6 animals/group, t-test, p = 0.018), while no alterations were found in the retrosplenial (46.7 ± 2.06/mm2 vs. 51.8 ± 3.7/mm2 in MD vs. control rats, n = 6 animals/group, ttest, p = 0.25) and motor (45.6 ± 2.29/mm2 vs. 47.2 ± 3.32/mm2 in MD vs. control rats, n = 6 animals/group, t-test, p = 0.7) cortices (Figures 1C,D)
We demonstrate an effect of early maternal deprivation on the decrease of marker expression by specific interneuron subpopulations in the hippocampus and prefrontal cortex
Summary
According to the neurodevelopmental theory of schizophrenia, this mental illness represents the end stage of a process that starts long before its clinical presentation and is caused by the combination of early life stress and genetic factors (Kinros et al, 2010; Rapoport et al, 2012; Bora, 2015). We used the P9 maternal deprivation model, as it has shown the strongest effects on behavior (Ellenbroek et al, 1998) when compared with earlier stress (at days 3 or 6). This model has shown a strong impact on increasing oxidative stress in the brains of affected animals (Markovic et al, 2017). Taken together, this MD protocol could be used to model some pathological features of schizophrenia
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