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Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway

Pregnenolone sulfate, an endogenous neurosteroid in the central nervous system, is a positive allosteric modulator of the NMDA receptor, and plays a role in the modulation of learning and memory. Here, we study the actions of pregnenolone sulfate using the dopamine transporter knockout (DAT-KO) mice...

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Autores principales: Wong, P, Sze, Y, Chang, C C R, Lee, J, Zhang, X
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354351/
https://www.ncbi.nlm.nih.gov/pubmed/25781227
http://dx.doi.org/10.1038/tp.2015.21
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author Wong, P
Sze, Y
Chang, C C R
Lee, J
Zhang, X
author_facet Wong, P
Sze, Y
Chang, C C R
Lee, J
Zhang, X
author_sort Wong, P
collection PubMed
description Pregnenolone sulfate, an endogenous neurosteroid in the central nervous system, is a positive allosteric modulator of the NMDA receptor, and plays a role in the modulation of learning and memory. Here, we study the actions of pregnenolone sulfate using the dopamine transporter knockout (DAT-KO) mice, which exhibit endophenotypes that recapitulate certain symptoms of schizophrenia, including the psychomotor agitation, stereotypy, prepulse inhibition (PPI) deficits and cognitive impairments. We found that acute treatment with pregnenolone sulfate normalized the hyperlocomotion and stereotypic bouts, and rescued the PPI deficits of DAT-KO mice. In addition, long-term treatment with pregnenolone sulfate rescued the cognitive deficits of DAT-KO mice in the novel object recognition and social transmission of food preference tests. We also showed that pregnenolone sulfate normalized behavioral abnormalities in MK801-treated wild-type mice, whereas pregnenolone, its precursor, only partially rescued MK801-induced behavioral abnormalities. This indicates that there are distinct mechanisms of action between pregnenolone sulfate and pregnenolone, and the involvement of NMDA receptor signaling in the action of pregnenolone sulfate. Moreover, we found that acute treatment with pregnenolone sulfate increased the phosphorylation levels of striatal AKT and GSK3β in DAT-KO mice, and that long-term treatment with pregnenolone sulfate increased expression levels of NR1 subunit of the NMDA receptor in hippocampus. Thus, pregnenolone sulfate was able to rescue the behavioral anomalies of DAT-KO mice through the NMDA receptor-mediated, AKT/GSK3β signaling pathway.
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spelling pubmed-43543512015-03-12 Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway Wong, P Sze, Y Chang, C C R Lee, J Zhang, X Transl Psychiatry Original Article Pregnenolone sulfate, an endogenous neurosteroid in the central nervous system, is a positive allosteric modulator of the NMDA receptor, and plays a role in the modulation of learning and memory. Here, we study the actions of pregnenolone sulfate using the dopamine transporter knockout (DAT-KO) mice, which exhibit endophenotypes that recapitulate certain symptoms of schizophrenia, including the psychomotor agitation, stereotypy, prepulse inhibition (PPI) deficits and cognitive impairments. We found that acute treatment with pregnenolone sulfate normalized the hyperlocomotion and stereotypic bouts, and rescued the PPI deficits of DAT-KO mice. In addition, long-term treatment with pregnenolone sulfate rescued the cognitive deficits of DAT-KO mice in the novel object recognition and social transmission of food preference tests. We also showed that pregnenolone sulfate normalized behavioral abnormalities in MK801-treated wild-type mice, whereas pregnenolone, its precursor, only partially rescued MK801-induced behavioral abnormalities. This indicates that there are distinct mechanisms of action between pregnenolone sulfate and pregnenolone, and the involvement of NMDA receptor signaling in the action of pregnenolone sulfate. Moreover, we found that acute treatment with pregnenolone sulfate increased the phosphorylation levels of striatal AKT and GSK3β in DAT-KO mice, and that long-term treatment with pregnenolone sulfate increased expression levels of NR1 subunit of the NMDA receptor in hippocampus. Thus, pregnenolone sulfate was able to rescue the behavioral anomalies of DAT-KO mice through the NMDA receptor-mediated, AKT/GSK3β signaling pathway. Nature Publishing Group 2015-03 2015-03-17 /pmc/articles/PMC4354351/ /pubmed/25781227 http://dx.doi.org/10.1038/tp.2015.21 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 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-sa/4.0/
spellingShingle Original Article
Wong, P
Sze, Y
Chang, C C R
Lee, J
Zhang, X
Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway
title Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway
title_full Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway
title_fullStr Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway
title_full_unstemmed Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway
title_short Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway
title_sort pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the akt/gsk3β pathway
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354351/
https://www.ncbi.nlm.nih.gov/pubmed/25781227
http://dx.doi.org/10.1038/tp.2015.21
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