NK₁ (TACR₁) receptor gene ‘knockout’ mouse phenotype predicts genetic association with ADHD

Abstract

Mice with functional genetic ablation of the Tacr1 (substance P-preferring receptor) gene (NK1R−/−) are hyperactive. Here, we investigated whether this is mimicked by NK1R antagonism and whether dopaminergic transmission is disrupted in brain regions that govern motor performance. The locomotor activity of NK1R−/− and wild-type mice was compared after treatment with an NK1R antagonist and/or psychostimulant (d-amphetamine or methylphenidate). The inactivation of NK1R (by gene mutation or receptor antagonism) induced hyperactivity in mice, which was prevented by both psychostimulants. Using in vivo microdialysis, we then compared the regulation of extracellular dopamine in the prefrontal cortex (PFC) and striatum in the two genotypes. A lack of functional NK1R reduced (>50%) spontaneous dopamine efflux in the prefrontal cortex and abolished the striatal dopamine response to d-amphetamine. These behavioural and neurochemical abnormalities in NK1R−/− mice, together with their atypical response to psychostimulants, echo attention deficit hyperactivity disorder (ADHD) in humans. These findings prompted genetic studies on the TACR1 gene (the human equivalent of NK1R) in ADHD patients in a case-control study of 450 ADHD patients and 600 screened supernormal controls. Four single-nucleotide polymorphisms (rs3771829, rs3771833, rs3771856, and rs1701137) at the TACR1 gene, previously known to be associated with bipolar disorder or alcoholism, were strongly associated with ADHD. In conclusion, our proposal that NK1R−/− mice offer a mouse model of ADHD was borne out by our human studies, which suggest that DNA sequence changes in and around the TACR1 gene increase susceptibility to this disorder.

The influence of test experience and NK1 receptor antagonists on the performance of NK1R-/- and wild type mice in the 5-Choice Serial Reaction-Time Task

“…Regulation of dopaminergic, noradrenergic and serotonergic transmission in corticostriatal brain regions is also disrupted in these mutant mice (Froger et al, 2001;Herpfer et al, 2005;Yan et al, 2011), as is thought to be the case in ADHD. Our proposal that NK1R-/-mice express the key signs of this disorder is supported by evidence for an association between polymorphisms in, or near, the TACR1 receptor gene (the human equivalent of the nk1R gene) and increased vulnerability to ADHD (Yan et al, 2010).…”

“…Spontaneous mutation(s) in wild type and/or NK1R-/-mice are also possible. Nevertheless, acute antagonism of NK1R does increase locomotor activity of the wild types (Yan et al, 2010) and so this behaviour, at least, is not affected by such confounding influences. Similarly, premature responses after treatment with L-5 were greater than after L-10, and lower after RP-10 than RP-5 in both wild types tested in the morning and NK1R-/-mice tested in the afternoon.…”

Inflammation: good or bad for ADHD?

“…Deletion of some of these genes in animals (e.g. SNAP25, TACR1) results in phenotypes suggesting a strong association with some of the ADHD symptoms (Mill et al 2004;Yan et al 2010). However, none of the genes implicated have been shown to be solely responsible for the complex behavioural pattern in ADHD.…”

Strengths and limitations of genetic models of ADHD

“…Thus, the limited construct validity and the ambiguous face and predictive validity of these mutants significantly question the use of these mice as a putative ADHD model. Recent preliminary investigations have suggested that the mice deficient in NK1 receptor (Yan et al 2010) and steroid sulfatase ) might be also relevant for ADHD, but a very limited information available at present prevents from the unambiguous categorization of these mice as putative models of ADHD.…”