Gene × environment interaction between latrophilin-3 (Lphn3 or Adgrl3) and developmental permethrin exposure in...

Attention deficit hyperactivity disorder (ADHD) occurs in 9.8% of U.S. children and has a large hereditary component arising from multiple gene variants. One of these is Latrophiln-3 (LPHN-3). Using CRISPR/Cas9 we deleted exon 3 in Sprague Dawley rats to create a global Lphn3 knockout (gKO). The gKO rats are hyperactive, startle hyper-reactive, impulsive, and have impaired working, spatial, and egocentric learning and memory. Permethrin (PRM) is a widely used pyrethroid insecticide. Acute exposure to PRM alters acoustic startle but its long-term effects from developmental exposure are unknown. The present experiment tested whether Lphn3 heterozygosity interacts with PRM developmental exposure to affect post exposure neurobehavior in rats. We used Lphn3^+/- (Het) rats since they have an intermediate phenotype compared with gKO rats that are severely affected (Regan et al., 2022). There were 4 groups: Lphn3-Het + PRM (120 mg/kg daily by gavage from postnatal day (P) 6-20 in 5 mL/kg corn oil (CO)), Lphn3-Het + CO, wildtype (WT) + PRM, and WT + CO. From 25 litters, 20-22 males and 20-22 females of each combination were obtained with not more than one male and one female from any given litter. Adult offspring were tested in an automated open-field for 1 h, in home-cage activity for 72 h, startle (including prepulse inhibition), novel object recognition (NOR), working memory (radial water maze (RWM)), spatial learning (Morris water maze (MWM)), and egocentric learning in the Cincinnati water maze (CWM). On acquisition and reversal probe trials in the MWM and on learning trials in the CWM, Lphn3-Het-PRM rats performed worse than other groups. In open-field, home-cage, startle, NOR, and RWM there were no interactions between Lphn3 and PRM but there were effects of Lphn3 heterozygosity. The results indicate that heterozygosity of the ADHD risk gene Lphn3 when combined with developmental exposure to PRM increases the adverse effects of either one alone.