A novel role for the ADHD risk gene latrophilin-3 in learning and memory in Lphn3 knockout rats

• Published in: Neurobiology of disease Vol. 158; p. 105456
• Main Authors: Regan, Samantha L., Pitzer, Emily M., Hufgard, Jillian R., Sugimoto, Chiho, Williams, Michael T., Vorhees, Charles V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2021; Elsevier
• Subjects: Adgrl-3; Animals; Attention Deficit Disorder with Hyperactivity - genetics; Cognition; Egocentric learning; Gene Knockout Techniques; Hippocampus - metabolism; Long-term potentiation; Long-Term Potentiation - genetics; Lphn3; Lphn3 knockout rat; Maze Learning; Novel object recognition; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - biosynthesis; Recognition, Psychology; Reflex, Startle - genetics; Spatial learning and memory; Spatial Memory; Long-term potentiation; Lphn3; Cognition; Egocentric learning; Novel object recognition; Spatial learning and memory; Adgrl-3; Lphn3 knockout rat
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2021.105456

Latrophilins (LPHNs) are adhesion G protein-coupled receptors with three isoforms but only LPHN3 is brain specific (caudate, prefrontal cortex, dentate, amygdala, and cerebellum). Variants of LPHN3 are associated with ADHD. Null mutations of Lphn3 in rat, mouse, zebrafish, and Drosophila result in hyperactivity, but its role in learning and memory (L&M) is largely unknown. Using our Lphn3 knockout (KO) rats we examined the cognitive abilities, long-term potentiation (LTP) in CA1, NMDA receptor expression, and neurohistology from heterozygous breeding pairs. KO rats were impaired in egocentric L&M in the Cincinnati water maze, spatial L&M and cognitive flexibility in the Morris water maze (MWM), with no effects on conditioned freezing, novel object recognition, or temporal order recognition. KO-associated locomotor hyperactivity had no effect on swim speed. KO rats had reduced early-LTP but not late-LTP and had reduced hippocampal NMDA-NR1 expression. In a second experiment, KO rats responded to a light prepulse prior to an acoustic startle pulse, reflecting visual signal detection. In a third experiment, KO rats given extra MWM pretraining and hidden platform overtraining showed no evidence of reaching WT rats' levels of learning. Nissl histology revealed no structural abnormalities in KO rats. LPHN3 has a selective effect on egocentric and allocentric L&M without effects on conditioned freezing or recognition memory. •Latrophilin-3 (Lphn3) is a synaptic adhesion GCPR involved in regulating signaling.•Variants of LPHN3 in humans are associated with some cases of ADHD.•Lphn3 KO rats are hyperactive and release more dopamine shown previously.•Here we show that Lphn3 KO rats have spatial and egocentric cognitive deficits.•Lphn3 KO rats also have impaired LTP and reduced NMDA-NR1 in hippocampus.