An assessment of executive function in two different rat models of attention‐deficit hyperactivity disorder: Spontaneously hypertensive versus Lphn3 knockout rats

• Published in: Genes, brain and behavior brain and behavior, 2021-11, Vol.20 (8), p.e12767-n/a
• Main Authors: Sable, Helen J. K., Lester, Deranda B., Potter, Joshua L., Nolen, Hunter G., Cruthird, Destinee M., Estes, Lauren M., Johnson, Alyssa D., Regan, Samantha L., Williams, Michael T., Vorhees, Charles V.
• Format: Article
• Language: English
• Subjects: Adgrl3; ADHD; Animal models; Animals; Attention Deficit Disorder with Hyperactivity - genetics; Attention Deficit Disorder with Hyperactivity - physiopathology; Attention deficit hyperactivity disorder; Children; CRISPR/Cas9; delayed spatial alternation; differential reinforcement of low rates; Disease Models, Animal; Etiology; Executive Function; externalizing behavior; Female; Gene Deletion; Genomes; Hyperactivity; Hypertension; Impulsive behavior; inhibitory control; Latrophilin‐3; Lphn3; Male; Mental task performance; Neurodevelopmental disorders; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Short term memory; Spatial Behavior; working memory
• ISSN: 1601-1848; 1601-183X
• DOI: 10.1111/gbb.12767

Attention‐deficit/hyperactivity disorder (ADHD) a common neurodevelopmental disorder of childhood and often comorbid with other externalizing disorders (EDs). There is evidence that externalizing behaviors share a common genetic etiology. Recently, a genome‐wide, multigenerational sample linked variants in the Lphn3 gene to ADHD and other externalizing behaviors. Likewise, limited research in animal models has provided converging evidence that Lphn3 plays a role in EDs. This study examined the impact of Lphn3 deletion (i.e., Lphn3−/−) in rats on measures of behavioral control associated with externalizing behavior. Impulsivity was assessed for 30 days via a differential reinforcement of low rates (DRL) task and working memory evaluated for 25 days using a delayed spatial alternation (DSA) task. Data from both tasks were averaged into 5‐day testing blocks. We analyzed overall performance, as well as response patterns in just the first and last blocks to assess acquisition and steady‐state performance, respectively. “Positive control” measures on the same tasks were measured in an accepted animal model of ADHD–the spontaneously hypertensive rat (SHR). Compared with wildtype controls, Lphn3−/− rats exhibited deficits on both the DRL and DSA tasks, indicative of deficits in impulsive action and working memory, respectively. These deficits were less severe than those in the SHRs, who were profoundly impaired on both tasks compared with their control strain, Wistar‐Kyoto rats. The results provide evidence supporting a role for Lphn3 in modulating inhibitory control and working memory, and suggest additional research evaluating the role of Lphn3 in the manifestation of EDs more broadly is warranted. Performance on a differential reinforcement of low rates (DRL) task and on a delayed spatial alternation (DSA) task was examined in Lphn3 knockout (KO) and wildtype (WT) rats as well as in Spontaneously Hypertensive Rats (SHR) and their control strain, Wistar‐Kyoto (WKY) rats. Compared to WTs, the Lphn3 KOs exhibited deficits on both the DRL and DSA tasks, indicative of deficits in impulsive action and working memory, respectively. These deficits were less severe than in the SHRs, who were profoundly impaired on both tasks compared to WKY rats.