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Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse

Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel pot...

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Autores principales: Feldcamp, L A, Boutros, P C, Raymond, R, Fletcher, P J, Nobrega, J N, Wong, A H C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534953/
https://www.ncbi.nlm.nih.gov/pubmed/28485732
http://dx.doi.org/10.1038/tp.2017.85
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author Feldcamp, L A
Boutros, P C
Raymond, R
Fletcher, P J
Nobrega, J N
Wong, A H C
author_facet Feldcamp, L A
Boutros, P C
Raymond, R
Fletcher, P J
Nobrega, J N
Wong, A H C
author_sort Feldcamp, L A
collection PubMed
description Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel potential treatment targets for schizophrenia, we searched for previously unknown molecular modulators of acoustic prepulse inhibition (PPI), a schizophrenia endophenotype, in the mouse. We examined six inbred mouse strains that have a range of PPI, and used microarrays to determine which mRNA levels correlated with PPI across these mouse strains. We examined several brain regions involved in PPI and schizophrenia: hippocampus, striatum, and brainstem, found a number of transcripts that showed good correlation with PPI level, and confirmed this with real-time quantitative PCR. We then selected one candidate gene for further study, Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1), because it is a putative enzyme that could metabolize catecholamine neurotransmitters, and thus might be a feasible target for new medications. We determined that Pdxdc1 mRNA and protein are both strongly expressed in the hippocampus and levels of Pdxdc1 are inversely correlated with PPI across the six mouse strains. Using shRNA packaged in a lentiviral vector, we suppressed Pdxdc1 protein levels in the hippocampus and increased PPI by 70%. Our results suggest that Pdxdc1 may regulate PPI and could be a good target for further investigation as a potential treatment for schizophrenia.
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spelling pubmed-55349532017-08-01 Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse Feldcamp, L A Boutros, P C Raymond, R Fletcher, P J Nobrega, J N Wong, A H C Transl Psychiatry Original Article Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel potential treatment targets for schizophrenia, we searched for previously unknown molecular modulators of acoustic prepulse inhibition (PPI), a schizophrenia endophenotype, in the mouse. We examined six inbred mouse strains that have a range of PPI, and used microarrays to determine which mRNA levels correlated with PPI across these mouse strains. We examined several brain regions involved in PPI and schizophrenia: hippocampus, striatum, and brainstem, found a number of transcripts that showed good correlation with PPI level, and confirmed this with real-time quantitative PCR. We then selected one candidate gene for further study, Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1), because it is a putative enzyme that could metabolize catecholamine neurotransmitters, and thus might be a feasible target for new medications. We determined that Pdxdc1 mRNA and protein are both strongly expressed in the hippocampus and levels of Pdxdc1 are inversely correlated with PPI across the six mouse strains. Using shRNA packaged in a lentiviral vector, we suppressed Pdxdc1 protein levels in the hippocampus and increased PPI by 70%. Our results suggest that Pdxdc1 may regulate PPI and could be a good target for further investigation as a potential treatment for schizophrenia. Nature Publishing Group 2017-05 2017-05-09 /pmc/articles/PMC5534953/ /pubmed/28485732 http://dx.doi.org/10.1038/tp.2017.85 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Article
Feldcamp, L A
Boutros, P C
Raymond, R
Fletcher, P J
Nobrega, J N
Wong, A H C
Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse
title Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse
title_full Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse
title_fullStr Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse
title_full_unstemmed Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse
title_short Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse
title_sort pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534953/
https://www.ncbi.nlm.nih.gov/pubmed/28485732
http://dx.doi.org/10.1038/tp.2017.85
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