Differences in 5-HT2A and mGlu2 Receptor Expression Levels and Repressive Epigenetic Modifications at the 5-HT2A Promoter Region in the Roman Low- (RLA-I) and High- (RHA-I) Avoidance Rat Strains

Abstract

The serotonin 2A (5-HT) and metabotropic glutamate 2 (mGlu2) receptors regulate each other and are associated with schizophrenia. The Roman high- (RHA-I) and the Roman low- (RLA-I) avoidance rat strains present well-differentiated behavioral profiles, with the RHA-I strain emerging as a putative genetic rat model of schizophrenia-related features. The RHA-I strain shows increased 5-HT and decreased mGlu2 receptor binding levels in prefrontal cortex (PFC). Here, we looked for differences in gene expression and transcriptional regulation of these receptors. The striatum (STR) was included in the analysis. 5-HT, 5-HT, and mGlu2 mRNA and [H]ketanserin binding levels were measured in brain homogenates. As expected, 5-HT binding was significantly increased in PFC in the RHA-I rats, while no difference in binding was observed in STR. Surprisingly, 5-HT gene expression was unchanged in PFC but significantly decreased in STR. mGlu2 receptor gene expression was significantly decreased in both PFC and STR. No differences were observed for the 5-HT receptor. Chromatin immunoprecipitation assay revealed increased trimethylation of histone 3 at lysine 27 (H3K27me3) at the promoter region of the HTR2A gene in the STR. We further looked at the Akt/GSK3 signaling pathway, a downstream point of convergence of the serotonin and glutamate system, and found increased phosphorylation levels of GSK3β at tyrosine 216 and increased β-catenin levels in the PFC of the RHA-I rats. These results reveal region-specific regulation of the 5-HT receptor in the RHA-I rats probably due to absence of mGlu2 receptor that may result in differential regulation of downstream pathways.

A Genetic Model of Impulsivity, Vulnerability to Drug Abuse and Schizophrenia-Relevant Symptoms With Translational Potential: The Roman High- vs. Low-Avoidance Rats

“…Notably, an interesting recent development is the finding that, compared with their RLA counterparts, RHA rats display a severe disruption of the dimeric metabotropic glutamate-2 (mGlu2)/5-HT2A receptor complex consisting in a dramatic reduction of the cortical, hippocampal and striatal density of mGlu2 receptors, associated with an increase of 5-HT2A receptor density in the frontal cortex (Klein et al, 2014; Fomsgaard et al, 2018). This molecular profile is reminiscent of what has been found in the cortex of drug-free schizophrenic patients (González-Maeso et al, 2008).…”

“…It is hypothesized that the lower activity and volume of the mPFC, the HC, and the AMY, together with the higher density of 5-HT2A receptors and the dramatically decreased density of mGlu2 receptors in the frontal cortex of RHA vs. RLA rats may determine a hyper-functional glutamatergic cortical system in RHA rats (Meyza et al, 2009; Klein et al, 2014; Río-Álamos et al, 2017a, 2019; Wood et al, 2017; Tapias-Espinosa et al, 2019). This in turn would elicit an increment in the functional tone of the dopaminergic VTA neurons projecting to the Acb (Elert, 2014) and a decrease in the functional tone of the mesocortical dopaminergic system of RHA rats (Dalley et al, 2007; Giorgi et al, 2007; Probst and van Eimeren, 2013; Tournier et al, 2013; Elert, 2014; Klein et al, 2014; Dalley and Robbins, 2017; Fomsgaard et al, 2018). In addition, the decreased density of DA D2 receptors together with the increased density in DA D1 receptors in the limbic system of RHAs relative to RLA rats (Giorgi et al, 1994, 2007; Guitart-Masip et al, 2006) may also contribute to the more robust functional tone of the mesolimbic dopaminergic system of the former line.…”

Schizophrenia-like reduced sensorimotor gating in intact inbred and outbred rats is associated with decreased medial prefrontal cortex activity and volume

“…Interestingly, compared with their RLA counterparts, RHA rats show spontaneous reductions in PPI, working memory [36] and latent inhibition [37]. These divergent behavioral profiles, together with differences in dopaminergic [38,39], serotoninergic, and glutamatergic systems [40][41][42], suggest that RHA rats may be a valid model of schizophrenia-related features. On the other hand, the outbred rat heterogeneous stock (hereafter, HS rats) was developed from a crossing of 8 inbred strains to obtain a stock of rats as heterogeneous as possible [43].…”

Coping-Style Behavior Identified by a Survey of Parent-of-Origin Effects in the Rat

“…Epigenetic modifications in the serotonin and glutamate receptors within in the prefrontal cortex differ between RLA and RHA rats, supporting the general principle that PoE might affect behavior via epigenetic effects in these strains ( Fomsgaard et al 2018 ). Besides differing in coping style, RHA and RLA rats exhibit different impulsivity, behavioral inhibition and behavioral flexibility.…”