Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers
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 synap...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996119301494 |
| _version_ | 1818734048882720768 |
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| author | Samantha L. Regan Jillian R. Hufgard Emily M. Pitzer Chiho Sugimoto Yueh-Chiang Hu Michael T. Williams Charles V. Vorhees |
| author_facet | Samantha L. Regan Jillian R. Hufgard Emily M. Pitzer Chiho Sugimoto Yueh-Chiang Hu Michael T. Williams Charles V. Vorhees |
| author_sort | Samantha L. Regan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T23:59:10Z |
| format | Article |
| id | doaj.art-c41c9e4579ce4005be30cbffbec39db8 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T23:59:10Z |
| publishDate | 2019-10-01 |
| publisher | Elsevier |
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| series | Neurobiology of Disease |
| spelling | doaj.art-c41c9e4579ce4005be30cbffbec39db82022-12-21T21:28:00ZengElsevierNeurobiology of Disease1095-953X2019-10-01130104494Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markersSamantha L. Regan0Jillian R. Hufgard1Emily M. Pitzer2Chiho Sugimoto3Yueh-Chiang Hu4Michael T. Williams5Charles V. Vorhees6Neuroscience Graduate Program, University of Cincinnati, United States of AmericaDepartment of Obstetrics and Gynecology, Indiana University School of Medicine, United States of AmericaNeuroscience Graduate Program, University of Cincinnati, United States of AmericaDepartment of Pediatrics, University of Cincinnati College of Medicine, Division of Neurology, Cincinnati Children's Hospital Medical Center, United States of AmericaDepartment of Pediatrics, University of Cincinnati College of Medicine, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States of AmericaDepartment of Pediatrics, University of Cincinnati College of Medicine, Division of Neurology, Cincinnati Children's Hospital Medical Center, United States of AmericaDepartment of Pediatrics, University of Cincinnati College of Medicine, Division of Neurology, Cincinnati Children's Hospital Medical Center, United States of America; Corresponding author at: Div. of Neurology, Cincinnati Children's Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229, United States of America.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.http://www.sciencedirect.com/science/article/pii/S0969996119301494Latrophilin-3 (LPHN3 or ADGRL(3))ADHDDopamine D1 receptor (DRD1)Tyrosine hydroxylaseAromatic amino acid decarboxylase (AADC)DARPP-32 |
| spellingShingle | Samantha L. Regan Jillian R. Hufgard Emily M. Pitzer Chiho Sugimoto Yueh-Chiang Hu Michael T. Williams Charles V. Vorhees Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers Neurobiology of Disease Latrophilin-3 (LPHN3 or ADGRL(3)) ADHD Dopamine D1 receptor (DRD1) Tyrosine hydroxylase Aromatic amino acid decarboxylase (AADC) DARPP-32 |
| title | Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers |
| title_full | Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers |
| title_fullStr | Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers |
| title_full_unstemmed | Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers |
| title_short | Knockout of latrophilin-3 in Sprague-Dawley rats causes hyperactivity, hyper-reactivity, under-response to amphetamine, and disrupted dopamine markers |
| title_sort | knockout of latrophilin 3 in sprague dawley rats causes hyperactivity hyper reactivity under response to amphetamine and disrupted dopamine markers |
| topic | Latrophilin-3 (LPHN3 or ADGRL(3)) ADHD Dopamine D1 receptor (DRD1) Tyrosine hydroxylase Aromatic amino acid decarboxylase (AADC) DARPP-32 |
| url | http://www.sciencedirect.com/science/article/pii/S0969996119301494 |
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