title: Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway.
abstract: 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.
authors.affiliation: 1] Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore [2] Department of Pharmacology, Neuroscience Phenotyping Core, National University of Singapore, Singapore, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: Wong
authors.affiliation: Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
authors.forename: Y
authors.initials: Y
authors.lastname: Sze
authors.affiliation: Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore.
authors.forename: C C R
authors.initials: CC
authors.lastname: Chang
authors.affiliation: 1] Office of Clinical Sciences, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore [2] Research Division, Institute of Mental Health, Singapore, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: 1] Program in Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore [2] Department of Physiology, National University of Singapore, Singapore, Singapore [3] Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011284:Pregnenolone / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C018370:pregnenolone sulfate; D011284:Pregnenolone; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3