Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain

Abstract

Dopamine 2 receptor (DRD2) is of major interest to the pathophysiology of schizophrenia (SCZ) both as a target for antipsychotic drug action as well as a SCZ-associated risk gene. The dopamine 1 receptor (DRD1) is thought to mediate some of the cognitive deficits in SCZ, including impairment of working memory that relies on normal dorsolateral prefrontal cortex (DLPFC) function. To better understand the association of dopamine receptors with SCZ, we studied the expression of three DRD2 splice variants and the DRD1 transcript in DLPFC, hippocampus and caudate nucleus in a large cohort of subjects (~700), including patients with SCZ, affective disorders and nonpsychiatric controls (from 14th gestational week to 85 years of age), and examined genotype-expression associations of 278 single-nucleotide polymorphisms (SNPs) located in or near DRD2 and DRD1 genes. Expression of D2S mRNA and D2S/D2-long (D2L) ratio were significantly increased in DLPFC of patients with SCZ relative to controls (P<0.0001 and P<0.0001, respectively), whereas D2L, D2Longer and DRD1 were decreased (P<0.0001). Patients with affective disorders showed an opposite pattern: reduced expression of D2S (major depressive disorder, P<0.0001) and increased expression of D2L and DRD1 (bipolar disorder, P<0.0001). Moreover, SCZ-associated risk alleles at rs1079727, rs1076560 and rs2283265 predicted increased D2S/D2L expression ratio (P<0.05) in control individuals. Our data suggest that altered splicing of DRD2 and expression of DRD1 may constitute a pathophysiological mechanism in risk for SCZ and affective disorders. The association between SCZ risk-associated polymorphism and the ratio of D2S/D2L is consistent with this possibility.

Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits

“…Assignment of rs2144025 as a regulatory variant was supported by a significant association with allelic mRNA expression observed in PFCs of schizophrenic and bipolar subjects, suggesting that the effects of rs2144025 be amplified in the disease state. Similar changes under pathophysiology had been observed for DRD2 SNPs that alter splicing [43], in opposite directions in normal subjects and schizophrenics [44], and ESR1 isoform expression had been shown to change in autopsy brain tissues from schizophrenics [12]. Supporting a role in behavioral modification, rs2144025 is associated with various psychological traits in four GWAS, in a sex and age dependent fashion in some but not all GWAS.…”

Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder

“…52,53 The downregulation of genes in energy pathways, particularly those from the mitochondrial electron transport chain, highlights another recurrent theme among transcriptomic studies of BD using brain and blood samples. 54 Many electron transport chain genes are also included in the pathway for Parkinson's disease, so it was not surprising to find enrichment of this pathway. Oxidative stress is considered to have an important role in the pathophysiology of Parkinson's, in which the specific loss of nigrostriatal dopaminergic neurons is a cellular hallmark.…”

Transcriptomic Analysis Shows Decreased Cortical Expression of NR4A1, NR4A2 and RXRB in Schizophrenia and Provides Evidence for Nuclear Receptor Dysregulation

“…Mutant mice, with ablation of RXRB-RXRG, RARB-RXRB or RARB-RXRG have shown locomotor defects and decrease of dopamine receptors DR1 and DR2 in the ventral striatum but not in the dorsal striatum [51]. There is evidence that suggests DRD2 is dysregulated in schizophrenia brains [52–54]. Krezel et al suggest that RXRB and RXRG may be functionally redundant in locomotion control [51], which is considered a functional readout of dopamine activity in the brain.…”