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Metabotropic Glutamate Receptor 2 and Dopamine Receptor 2 Gene Expression Predict Sensorimotor Gating Response in the Genetically Heterogeneous NIH-HS Rat Strain

  • Tina Becher Østerbøg
  • Doan Minh On
  • Ignasi Oliveras
  • Cristóbal Río-Álamos
  • Ana Sanchez-Gonzalez
  • Carles Tapias-Espinosa
  • Adolf Tobeña
  • Javier González-Maeso
  • Alberto Fernández-TeruelEmail author
  • Susana AznarEmail author
Article
  • 63 Downloads

Abstract

Disruption of sensorimotor gating causes “flooding” of irrelevant sensory input and is considered a congenital trait in several neurodevelopmental disorders. Prepulse inhibition of acoustic startle response (PPI) is the operational measurement and has a high translational validity. Pharmacological studies in rodents have linked alterations in serotonin, dopamine and glutamate signalling to PPI disruption. How PPI response is associated with gene expression levels of these receptors is unknown. PPI response was assessed in 39 genetically heterogeneous National Institutes of Health-Heterogeneous Stock (NIH-HS) rats. Animals were classified as high, medium or low PPI. Expression levels of glutamate metabotropic receptor 2 (Grm2), dopamine receptor D2 (Drd2), dopamine receptor D1 (Drd1), serotonin receptor 1A (Htr1a), serotonin receptor 2A (Htr2a) and homer scaffolding protein 1 (Homer1) were investigated in prefrontal cortex (PFC) and striatum (STR). When comparing the two extreme phenotypes, only Drd2 in STR showed increased expression in the low PPI group. A multinomial model fitting all genes and all groups indicated that Grm2 in PFC, and Grm2 and Drd2 in the STR predicted PPI group. This was corroborated by a linear relationship of Grm2 with PPI in PFC, and Drd2 with PPI in STR. An interaction between levels of H3K27 trimethylation, associated with transcriptional repression, and PPI phenotype was observed for Drd2 in STR. Gene set enrichment analysis on a microarray dataset on Lewis rats confirmed enrichment of Drd2 in PFC in relation to PPI. These findings contribute to the understanding of the genetic substrate behind alterations in sensorimotor gating, relevant for its linkage to neurodevelopmental disorders.

Keywords

Sensorimotor gating response Schizophrenia Neurotransmitter receptors Postsynapse Gene expression Epigenetics 

Notes

Funding Information

This study was partially supported by grants PSI2017-82257-P (MINECO), 2014SGR-1587 and “ICREA-Academia 2013” [to A.F-T], and by the following Ph.D. fellowships: FPI [to A.S-G.] and FI [to I.O.]. JGM is supported by National Institute of Health grants R01MH084894 and R01MH111940. SA received supporting grants from the Research Council of Bispebjerg-Frederiksberg Hospital and Oda og Hans Svenningsens Fond.

Compliance with Ethical Standards

Experiments were performed in accordance with the Spanish legislation on “Protection of Animals Used for Experimental and Other Scientific Purposes” and the European Communities Council Directive (2010/63/EU) on this subject. Every effort was made to minimize any suffering of the animals used in this study.

Conflict of Interest

The authors declare that there is no conflict of interest.

Supplementary material

12035_2019_1829_MOESM1_ESM.docx (100 kb)
ESM 1 (DOCX 99 kb)

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Authors and Affiliations

  1. 1.Research Laboratory for Stereology and NeuroscienceCopenhagen University Hospital, Bispebjerg and FrederiksbergCopenhagenDenmark
  2. 2.Department of Physiology and BiophysicsVirginia Commonwealth University School of MedicineRichmondUSA
  3. 3.Department of Psychiatry and Forensic Medicine, Medical Psychology Unit, School of MedicineInstituto de Neurociencias, Universidad Autónoma de BarcelonaBarcelonaSpain
  4. 4.Department of PsychologyAustral University of ChileValdiviaChile
  5. 5.Copenhagen Center for Translational ResearchCopenhagen University Hospital, Bispebjerg and FrederiksbergCopenhagenDenmark

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