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Neurobiol Dis. 2019 Oct;130:104494. doi: 10.1016/j.nbd.2019.104494. Epub 2019 Jun 6.

Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers.

Author information

1
Neuroscience Graduate Program, University of Cincinnati, United States of America.
2
Department of Obstetrics and Gynecology, Indiana University School of Medicine, United States of America.
3
Department of Pediatrics, University of Cincinnati College of Medicine, Division of Neurology, Cincinnati Children's Hospital Medical Center, United States of America.
4
Department of Pediatrics, University of Cincinnati College of Medicine, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States of America.
5
Department of Pediatrics, University of Cincinnati College of Medicine, Division of Neurology, Cincinnati Children's Hospital Medical Center, United States of America. Electronic address: charles.vorhees@cchmc.org.

Abstract

Attention deficit hyperactivity disorder is a pervasive developmental disorder characterized by inattention, impulsivity, and hyperactivity and is 75-90% heritable. Latrophilin-3 (LPHN3; or ADGRL(3)) is associated with a subtype of ADHD, but how it translates to symptoms is unknown. LPHN3 is a synaptic adhesion G protein coupled receptor that binds to fibronectin leucine rich transmembrane protein 3 and teneurin-3 (FLRT3 and TEN-3). We created a null mutation of Lphn3 (KO) in Sprague-Dawley rats using CRISPR/Cas9 to delete exon-3. The KO rats had no effects on reproduction or survival but reduced growth. KO females showed catch-up weight gain whereas KO males did not. We tested WT and KO littermates for home-cage activity, anxiety-like behavior, acoustic startle response, and activity after amphetamine challenge. Expression of Lphn3-related genes, monoamines, and receptors were determined. Lphn3 KO rats showed persistent hyperactivity, increased acoustic startle, reduced activity in response to amphetamine relative to baseline, and female-specific reduced anxiety-like behavior. Expression of Lphn1, Lphn2, and Flrt3 by qPCR and their protein products by western-blot analysis showed no compensatory upregulation. Striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase (AADC), and the dopamine transporter were increased and dopamine D1 receptor (DRD1) and dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) decreased with no changes in DRD2, DRD4, vesicular monoamine transporter-2, N-methyl-d-aspartate (NMDA)-NR1, -NR2A, or -NR2B. LPHN3 is expressed in many brain regions but its function is largely unknown. Data from human, mouse, zebrafish, Drosophila and our new Lphn3 KO rat data collectively show that its disruption is significantly correlated with hyperactivity and associated striatal changes in dopamine markers.

KEYWORDS:

ADHD; Aromatic amino acid decarboxylase (AADC); DARPP-32; Dopamine D1 receptor (DRD1); Dopamine transporter (DAT); Latrophilin-3 (LPHN3 or ADGRL(3)); Tyrosine hydroxylase

PMID:
31176715
PMCID:
PMC6689430
[Available on 2020-10-01]
DOI:
10.1016/j.nbd.2019.104494

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