Abstract
Reelin depletion and stress seem to affect similar pathways including GABAergic and glutamatergic signaling and both are implicated in psychiatric disorders in late adolescence/early adulthood. The interaction between reelin depletion and stress, however, remains unclear. To investigate this, male and female heterozygous reelin mice (HRM) and wildtype (WT) controls were treated with the stress hormone, corticosterone (CORT), during late adolescence to simulate chronic stress. Glucocorticoid receptors (GR), N-methyl-d-aspartate receptor (NMDAr) subunits, glutamic acid decarboxylase (GAD67) and parvalbumin (PV) were measured in the hippocampus and the prefrontal cortex (PFC) in adulthood. While no changes were seen in male mice, female HRM showed a significant reduction in GR expression in the dorsal hippocampus. In addition, CORT reduced GR levels as well as GluN2B and GluN2C subunits of NMDAr in the dorsal hippocampus in female mice only. CORT furthermore reduced GluN1 levels in the PFC of female mice. The combined effect of HRM and CORT treatment appeared to be additive in terms of GR expression in the dorsal hippocampus. Female-specific CORT-induced changes were associated with overall higher circulating CORT levels in female compared to male mice. This study shows differential effects of reelin depletion and CORT treatment on GR and NMDAr protein expression in male and female mice, suggesting that females are more susceptible to reelin haploinsufficiency as well as late-adolescent stress. These findings shed more light on female-specific vulnerability to stress and have implications for stress-associated mental illnesses with a female bias including anxiety and major depression.
Highlights
Reelin is an extracellular matrix protein that is secreted by Cajal-Retzius cells during embryonic brain development and mainly by cortical and hippocampal GABAergic interneurons during adulthood [1,2,3]
Aside from its developmental role, reelin serves a crucial function in the mature brain acting through its two major receptors, Apolipoprotein E receptor 2 (EpoER2) and very low-density lipoprotein receptor (VLDLR) [12], activating numerous downstream cascades via Dab1 phosphorylation such as Akt/mTOR or N-WASP leading to microtubule formation and actin stabilization, respectively [13]
We have previously shown that heterozygous reelin mice (HRM) were more susceptible to CORT treatment with regards to spatial memory [37], it remains unclear how reelin deficiency may increase susceptibility to stress on the molecular level
Summary
Reelin is an extracellular matrix protein that is secreted by Cajal-Retzius cells during embryonic brain development and mainly by cortical and hippocampal GABAergic interneurons during adulthood [1,2,3]. Brain Sci. 2018, 8, 118 induces a less severe phenotype showing dendritic abnormalities in the cortex and the hippocampus and only subtle abnormalities in cognitive function [5,6,7,8,9] These mice are used to investigate the role of reelin in the development of psychiatric disorders as mutations in the reelin gene as well as decreased levels of mRNA are associated with autism [10], schizophrenia and bipolar disorder [2,11]. This study sought to investigate a) how reelin deficiency or adolescent stress impact the expression of NMDA receptor subunits, the GABAergic markers, GAD67 and PV, as well as GR and b) whether reelin deficiency makes the brain more vulnerable to adolescent/early adult stress which may explain the profound decrease in those markers in psychiatric disorders. We hypothesized that the combined effect of reelin haploinsufficiency and adolescent CORT treatment would cause alterations in GABAergic, glutamatergic and stress receptor pathways but these may be differentially modulated according to sex
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
