Gnal (Golf) is known to be coupled to the dopamine receptor, DRD1, and plays a major role in excitatory dopamine transmission in the striatum. This is particularly relevant since significant relationships have been observed between certain SNPs in Gnal and symptoms of inattention and hyperactivity/impulsiveness in ADHD children (Laurin, Ickowicz et al., 2008
Based on blood samples, no between-strain differences were observed in either the DRD2 or DRD4 genes, suggesting that neither gene is likely to mediate the behavioral differences observed between the WKY and SHR strains. In contrast, WKY/SHR differences were observed in the 3rd exon of DAT1. Whilst these mutations do not result in direct amino-acid changes to the DAT protein, it is possible that they mediate some other process that explains the differences in DAT expression and function observed between the two strains (Mill, Sagvolden et al., 2005
The dopamine receptor D1 interacting protein (DRD1ip
, calcyon) represents a brain-specific DRD1-interacting protein involved in DRD1/DRD5 receptor-mediated calcium signaling. In our data, the SHR/NCrl had two-fold increased expression of calcyon mRNA compared to WKY/NHsd rats, which is in agreement with a recent study which examined calcyon mRNA expression in the frontal-striatal circuitry of 3-, 5-, and 10-week-old SHR and WKY rats (Heijtz, Alexeyenko et al., 2007
A major dopaminergic function is to modulate fast, ionotropic synaptic transmission. The observed changes in gene expression for both AMPA receptor and NMDA receptor subunits may profoundly affect neuronal function. Electrophysiological studies revealed two potential consequences of such changes (Jensen, Rinholm et al., 2009
). Firstly, in male SHR/NCrl and WKY/NHsd rats at postnatal day 28, AMPA receptor–mediated transmission at the CA3-to-CA1 synapses in stratum radiatum of the hippocampus was significantly reduced. Secondly, the NMDAR containing Grin2b (aka GluN2B) subunits contributed substantially to induction of LTP in SHR/NCrl, but not in WKY/NHsd. In human ADHD, there is evidence for genetic polymorphism of both Grin2a and Grin2b subunits of the NMDA receptor (Turic et al. 2004; Dorval et al. 2007).
Human and animal data indicate that the mu opioid receptor 1 (Oprm1) is associated with substance abuse disorders (Berrendero, Kieffer et al., 2002
; Zhang, Kendler et al., 2006
). Individuals with ADHD, depending on the subtype, also show strong substance dependence (Faraone, Adamson et al., 2007
; Rodriguez, Tercyak et al., 2008
). Thus, it is possible that substance dependence in ADHD may be modulated by Oprm1.
SHR/NCrl rats also showed significant changes in the expression of Hexokinase1 (Hk1) and Casein kinase 1, alpha 1 (Csnk1a1) compared to WKY/NHsd rats. Hk1 catalyzes the first step in glucose metabolism. Expression levels of Hk1 in SHR/NCrl rats may be a reflection of the basal physiological glucose metabolism, and thus basal neuronal activity. The neuronal energetics aspect of these findings is supported by a common observable feature of ADHD - marked moment-to-moment fluctuation in task performance. This fluctuation may arise from deficient lactate production and supply by astrocytes to rapidly firing neurons (Russell, Oades et al., 2006
The transcripts Lhx1 and Hes6 show evidence of significant modulation in SHR/NCrl. Hes6 belongs to the basic helix-loop-helix family (bHLH) of transcription factors and is known to be involved in cortical neurogenesis. Lhx1 plays an important role in Purkinje cell generation and differentiation (Zhao, Kwan et al., 2007
). Thus, changes in the expression of these genes could affect forebrain and hindbrain circuitry in the SHR/NCrl. Although there is no known evidence connecting these genes directly to ADHD, it can be speculated that altered expression levels of these genes might affect cortical and cerebellar volumes in SHRs by influencing neurogenesis and differentiation. Such changes would be consistent with those reported in individuals with ADHD (Valera, Faraone et al., 2007
The aquaporins are a family of water-selective membrane channels found in animals, plants, and microorganisms. Aqp4 is the predominant water channel in the brain and has an important role in brain water homeostasis. Aqp4 is significantly down-regulated in the SHR/NCrl (DasBanerjee, Middleton et al., 2008