The Effect of Early Life Stress on Emotional Behaviors in GPR37KO Mice.

Vasco Sousa,Xiaoqun Zhang,Per Svenningsson,Vandana Veenit,Antonio Ambrosini

doi:10.3390/ijms23010410

Vasco Sousa, Xiaoqun Zhang + Show 3 more

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https://doi.org/10.3390/ijms23010410

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Abstract

GPR37 is an orphan G-protein-coupled receptor, a substrate of parkin which is linked to Parkinson’s disease (PD) and affective disorders. In this study, we sought to address the effects of early life stress (ELS) by employing the paradigm of limited nesting material on emotional behaviors in adult GPR37 knockout (KO) mice. Our results showed that, while there was an adverse effect of ELS on various domains of emotional behaviors in wild type (WT) mice in a sex specific manner (anxiety in females, depression and context-dependent fear memory in males), GPR37KO mice subjected to ELS exhibited less deteriorated emotional behaviors. GPR37KO female mice under ELS conditions displayed reduced anxiety compared to WT mice. This was paralleled by lower plasma corticosterone in GPR37KO females and a lower increase in P-T286-CaMKII by ELS in the amygdala. GPR37KO male mice, under ELS conditions, showed better retention of hippocampal-dependent emotional processing in the passive avoidance behavioral task. GPR37KO male mice showed increased immobility in the forced swim task and increased P-T286-CaMKII in the ventral hippocampus under baseline conditions. Taken together, our data showed overall long-term effects of ELS—deleterious or beneficial depending on the genotype, sex of the mice and the emotional context.

Highlights

GPR37 is an orphan G-protein-coupled receptor which is highly expressed in the brain [1,2,3]
Given the association of GPR37 with Parkinson disease [23] and based on the evidence showing the link between abnormal Ca2+-calmodulin independent protein kinase II (CaMKII) function with motor deficits and synaptic deficits in experimental parkinsonism [24], we examined protein levels of phosphorylated alpha CaMKII-(P)-T286CaMKIIand total CaMKII in the hippocampus and amygdala of these mice in the aftermath of all the behavioral tests
Post hoc analysis using the two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli revealed that the wild type (WT) early life stress (ELS) female group condition exhibited a reduced frequency of entering the open arms compared to the WT no-ELS female group (Figure 2A, p < 0.05), while KO ELS females showed a tendency to make more visits to open arms

Summary

Introduction

GPR37 is an orphan G-protein-coupled receptor which is highly expressed in the brain [1,2,3]. GPR37 is called parkin-associated endothelin B-like receptor (PAEL-R), owing to its connection with parkin and its homology with the endothelin B receptor [4]. GPR37 can support or hinder neuronal viability depending upon its folding and cellular localization [5,6]. The surface expression of the receptor exhibits neuroprotective properties while the intracellular retention of the protein causes misfolding, aggregation, and degeneration [4]. Studies focusing on the dopaminergic system in GPR37 knockout (KO) mice demonstrate a decrease in dopamine content in the striatum, dysregulated dopaminergic signaling in the brain and specific deficits in motor behavior sensitive to nigrostriatal dysfunction [8,9,10,11]

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