Impulsivity is a heritable trait in rodents and associated with a novel quantitative trait locus on chromosome 1.

Impulsivity describes the tendency to act prematurely without appropriate foresight and is symptomatic of a number of neuropsychiatric disorders. Although a number of genes for impulsivity have been identified, no study to date has carried out an unbiased, genome-wide approach to identify genetic markers associated with impulsivity in experimental animals. Herein we report a linkage study of a six-generational pedigree of adult rats phenotyped for one dimension of impulsivity, namely premature responding on the five-choice serial reaction time task, combined with genome wide sequencing and transcriptome analysis to identify candidate genes associated with the expression of the impulsivity trait. Premature responding was found to be heritable (h2 = 13-16%), with significant linkage (LOD 5.2) identified on chromosome 1. Fine mapping of this locus identified a number of polymorphic candidate genes, however only one, beta haemoglobin, was differentially expressed in both the founder strain and F6 generation. These findings provide novel insights into the genetic substrates and putative neurobiological mechanisms of impulsivity with broader translational relevance for impulsivity-related disorders in humans.

Effects of haloperidol and clozapine on synapse-related gene expression in specific brain regions of male rats.

We investigated the effects of clozapine and haloperidol, drugs that are widely used in the treatment of schizophrenia, on gene expression in six cortical and subcortical brain regions of adult rats. Drug treatments started at postnatal day 85 and continued over a 12-week period. Ten animals received haloperidol (1 mg/kg bodyweight) and ten received clozapine (20 mg/kg bodyweight) orally each day. Ten control rats received no drugs. The ten genes selected for this study did not belong to the dopaminergic or serotoninergic systems, which are typically targeted by the two substances, but coded for proteins of the cytoskeleton and proteins belonging to the synaptic transmitter release machinery. Quantitative real-time PCR was performed in the prelimbic cortex, cingulate gyrus (CG1) and caudate putamen and in the hippocampal cornu ammonis 1 (CA1), cornu ammonis 3 (CA3) and dentate gyrus. Results show distinct patterns of gene expression under the influence of the two drugs, but also distinct gene regulations dependent on the brain regions. Haloperidol-medicated animals showed statistically significant downregulation of SNAP-25 in CA3 (p = 0.0134) and upregulation of STX1A in CA1 (p = 0.0133) compared to controls. Clozapine-treated animals showed significant downregulation of SNAP-25 in CG1 (p = 0.0013). Our results clearly reveal that the drugs' effects are different between brain regions. These effects are possibly indirectly mediated through feedback mechanisms by proteins targeted by the drugs, but direct effects of haloperidol or clozapine on mechanisms of gene expression cannot be excluded.

A common functional allele of the Nogo receptor gene, reticulon 4 receptor (RTN4R), is associated with sporadic amyotrophic lateral sclerosis in a French population.

Amyotrophic lateral sclerosis is sporadic (SALS) in 90% of cases and has complex environmental and genetic influences. Nogo protein inhibits neurite outgrowth and is overexpressed in muscle in ALS. Our aims were to study the reticulon 4 receptor gene RTN4R which encodes Nogo 1 receptor (NgR1) in SALS, to test if the variants were associated with variable expression of the gene and whether NgR1 protein expression was modified in a transgenic mouse model of ALS. We genotyped three single nucleotide polymorphisms (SNPs; rs701421, rs701427, and rs1567871) of the RTN4R gene in 364 SALS French patients and 430 controls. We examined expression of RTN4R mRNA by quantitative PCR in control post mortem human brain tissue. We determined the expression of NgR1 protein in spinal motor neurons from a SOD1 G86R ALS mouse model. We observed significant associations between SALS and RTN4R alleles. Messenger RNA expression from RTN4R in human cortical brain tissue correlated significantly with the genotypes of rs701427. NgR1 protein expression was reduced in Nogo A positive motor neurons from diseased transgenic animals. In conclusion, these observations suggest that a functional RTN4R gene variant is associated with SALS. This variant may act in concert with other genetic variants or environmental influences.

RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release.

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca(2+)-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2(-/-) mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2(-/-) mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I(A) potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.