adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment

Abstract

Externalizing disorders (ED) are a cause of concern for public health, and their high heritability makes genetic risk factors a priority for research. Adhesion G-Protein-Coupled Receptor L3 (ADGRL3) is strongly linked to several EDs, and loss-of-function models have shown the impacts of this gene on several core ED-related behaviors. For example, adgrl3.1−/− zebrafish show high levels of hyperactivity. However, our understanding of the mechanisms by which this gene influences behavior is incomplete. Here we characterized, for the first time, externalizing behavioral phenotypes of adgrl3.1−/− zebrafish and found them to be highly impulsive, show risk-taking in a novel environment, have attentional deficits, and show high levels of hyperactivity. All of these phenotypes were rescued by atomoxetine, demonstrating noradrenergic mediation of the externalizing effects of adgrl3.1. Transcriptomic analyses of the brains of adgrl3.1−/− vs. wild-type fish revealed several differentially expressed genes and enriched gene clusters that were independent of noradrenergic manipulation. This suggests new putative functional pathways underlying ED-related behaviors, and potential targets for the treatment of ED.

Validation of L-Type Calcium Channel Blocker Amlodipine as a Novel ADHD Treatment through Cross-Species Analysis, Drug-Target Mendelian Randomization, and clinical evidence from medical records

“…We have previously shown that zebrafish lacking the adhesion G-protein coupled receptor latrophilin 3 ( adgrl3.1 -/- ) show increased hyperactivity in the open field and increased impulsivity in the 5-CSRTT. 10 Like in SHR rats, we previously found that amlodipine effectively rescues hyperactive phenotype in adgrl3.1 -/- zebrafish 7 models of ADHD. Here, we tested the hypothesis that amlodipine would also reduce impulsivity in ADHD zebrafish models in the 5-CSRTT - an assay specifically designed to gauge impulsivity 13 and pharmacologically validated in adgrl3.1 -/- ADHD models.…”

“…Here, we tested the hypothesis that amlodipine would also reduce impulsivity in ADHD zebrafish models in the 5-CSRTT - an assay specifically designed to gauge impulsivity 13 and pharmacologically validated in adgrl3.1 -/- ADHD models. 10 There were no differences in Phase 2 training between wild-type (WT) and adgrl3.1 -/- (main effect Strain LMM: F [1,297.06] = 0.09, p = 0.769). During baseline 5-CSRTT Phase 2 (pre-drug treatment), adgrl3.1 -/- fish showed more premature responses than WT, t (40.45) = 2.02, p = 0.05, 95%CI = 0 - 0.1 (Figure 2B).…”

“…Adult adgrl3.1 -/- show high levels of impulsivity in the 5-CSRTT, which is rescued with atomoxetine. 10 Here, we trained adult adgrl3.1 -/- zebrafish (nD=D48; power analyses based on previous work from our group showing medium-large effect sizes on the 5-CSRTT (Figure 2 A), 10 a validated test for measuring impulsivity in zebrafish. 13 The task involves training the fish to respond to a light stimulus in one of five locations in a specialized testing arena (Zantiks AD, Cambridge, UK).…”

“…8 Second, we determined if the compounds are effective for rescuing impulsivity (not only hyperactivity) using the 5-Choice Serial Reaction Time Task (5-CSRTT) in adult mutant zebrafish. 9,10 We show effects of other L-type calcium channel blockers (LTCCBs), determine brain penetration and effects on c-Fos expression. Finally, we determine human translational value using Mendelian randomization (MR) 11,12 and by assessing the effect of amlodipine on mental health questionnaire responses associated with high ADHD polygenic risk scores (PRS).…”

Why we need neurodiversity in brain and behavioral sciences

“…Similarly, genetic links between ADHD and the immune system established by Fontana et al could help develop medical interventions; however, these interventions may overlook the strengths and contributions of those with ADHD. [7] Transcranial magnetic stimulation for bipolar disorder, as researched by Levenberg and Cordner, [8] and the 'Multitudes' digital assessment tool for dyslexia developed by UCSF in 2022 represent significant strides in their respective interventions. Yet, they also exemplify the medical model's tendency to view neurodivergent conditions as problems in need of solutions.…”