Cargando…

Latrophilin‐3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity

Latrophilin‐3 (LPHN3) is a brain specific G‐protein coupled receptor associated with increased risk of attention deficit hyperactivity disorder (ADHD) and cognitive deficits. CRISPR/Cas9 was used to generate a constitutive knockout (KO) rat of Lphn3 by deleting exon 3, based on human data that LPHN3...

Descripción completa

Detalles Bibliográficos
Autores principales: Regan, Samantha L., Sugimoto, Chiho, Dawson, Hannah E., Williams, Michael T., Vorhees, Charles V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9744505/
https://www.ncbi.nlm.nih.gov/pubmed/35985692
http://dx.doi.org/10.1111/gbb.12817
_version_ 1784848940150030336
author Regan, Samantha L.
Sugimoto, Chiho
Dawson, Hannah E.
Williams, Michael T.
Vorhees, Charles V.
author_facet Regan, Samantha L.
Sugimoto, Chiho
Dawson, Hannah E.
Williams, Michael T.
Vorhees, Charles V.
author_sort Regan, Samantha L.
collection PubMed
description Latrophilin‐3 (LPHN3) is a brain specific G‐protein coupled receptor associated with increased risk of attention deficit hyperactivity disorder (ADHD) and cognitive deficits. CRISPR/Cas9 was used to generate a constitutive knockout (KO) rat of Lphn3 by deleting exon 3, based on human data that LPHN3 variants are associated with some cases of ADHD. Lphn3 KO rats are hyperactive with an attenuated response to ADHD medication and have cognitive deficits. Here, we tested KO, heterozygous (HET), and wildtype (WT) rats to determine if there was a gene‐dosage effect. We tested the rats in home‐cage activity starting at postnatal day (P)35 and P50, followed by tests of egocentric learning (Cincinnati water maze [CWM]), spatial learning (Morris water maze [MWM]), working memory (radial water maze [RWM]), incidental learning (novel object recognition [NOR]), acoustic startle response (ASR) habituation, tactile startle response (TSR) habituation, prepulse modification of acoustic startle, shuttle‐box passive avoidance, conditioned freezing, and a mirror image version of the CWM. KO and HET rats were hyperactive. KO and HET rats had egocentric (CWM) and spatial deficits (MWM), increased startle response, and KO rats showed less conditioned freezing on contextual and cued memory; there were no effects on working memory (RWM) or passive avoidance. The selective gene‐dosage effect in Lphn3 HET rats indicates that Lphn3 exhibits dominate expression on functions where it is most abundantly expressed (striatum, hippocampus) but not on behaviors mediated by regions of low expression. The data add further evidence to the impact of this synaptic protein on brain function and behavior.
format Online
Article
Text
id pubmed-9744505
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Blackwell Publishing Ltd
record_format MEDLINE/PubMed
spelling pubmed-97445052023-02-08 Latrophilin‐3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity Regan, Samantha L. Sugimoto, Chiho Dawson, Hannah E. Williams, Michael T. Vorhees, Charles V. Genes Brain Behav Original Articles Latrophilin‐3 (LPHN3) is a brain specific G‐protein coupled receptor associated with increased risk of attention deficit hyperactivity disorder (ADHD) and cognitive deficits. CRISPR/Cas9 was used to generate a constitutive knockout (KO) rat of Lphn3 by deleting exon 3, based on human data that LPHN3 variants are associated with some cases of ADHD. Lphn3 KO rats are hyperactive with an attenuated response to ADHD medication and have cognitive deficits. Here, we tested KO, heterozygous (HET), and wildtype (WT) rats to determine if there was a gene‐dosage effect. We tested the rats in home‐cage activity starting at postnatal day (P)35 and P50, followed by tests of egocentric learning (Cincinnati water maze [CWM]), spatial learning (Morris water maze [MWM]), working memory (radial water maze [RWM]), incidental learning (novel object recognition [NOR]), acoustic startle response (ASR) habituation, tactile startle response (TSR) habituation, prepulse modification of acoustic startle, shuttle‐box passive avoidance, conditioned freezing, and a mirror image version of the CWM. KO and HET rats were hyperactive. KO and HET rats had egocentric (CWM) and spatial deficits (MWM), increased startle response, and KO rats showed less conditioned freezing on contextual and cued memory; there were no effects on working memory (RWM) or passive avoidance. The selective gene‐dosage effect in Lphn3 HET rats indicates that Lphn3 exhibits dominate expression on functions where it is most abundantly expressed (striatum, hippocampus) but not on behaviors mediated by regions of low expression. The data add further evidence to the impact of this synaptic protein on brain function and behavior. Blackwell Publishing Ltd 2022-08-19 /pmc/articles/PMC9744505/ /pubmed/35985692 http://dx.doi.org/10.1111/gbb.12817 Text en © 2022 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Regan, Samantha L.
Sugimoto, Chiho
Dawson, Hannah E.
Williams, Michael T.
Vorhees, Charles V.
Latrophilin‐3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity
title Latrophilin‐3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity
title_full Latrophilin‐3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity
title_fullStr Latrophilin‐3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity
title_full_unstemmed Latrophilin‐3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity
title_short Latrophilin‐3 heterozygous versus homozygous mutations in Sprague Dawley rats: Effects on egocentric and allocentric memory and locomotor activity
title_sort latrophilin‐3 heterozygous versus homozygous mutations in sprague dawley rats: effects on egocentric and allocentric memory and locomotor activity
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9744505/
https://www.ncbi.nlm.nih.gov/pubmed/35985692
http://dx.doi.org/10.1111/gbb.12817
work_keys_str_mv AT regansamanthal latrophilin3heterozygousversushomozygousmutationsinspraguedawleyratseffectsonegocentricandallocentricmemoryandlocomotoractivity
AT sugimotochiho latrophilin3heterozygousversushomozygousmutationsinspraguedawleyratseffectsonegocentricandallocentricmemoryandlocomotoractivity
AT dawsonhannahe latrophilin3heterozygousversushomozygousmutationsinspraguedawleyratseffectsonegocentricandallocentricmemoryandlocomotoractivity
AT williamsmichaelt latrophilin3heterozygousversushomozygousmutationsinspraguedawleyratseffectsonegocentricandallocentricmemoryandlocomotoractivity
AT vorheescharlesv latrophilin3heterozygousversushomozygousmutationsinspraguedawleyratseffectsonegocentricandallocentricmemoryandlocomotoractivity