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Positive symptom phenotypes appear progressively in “EDiPS”, a new animal model of the schizophrenia prodrome

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Alice Petty, Xiaoying Cui, Asad Ali, Zilong Du, Sunil Srivastav, James P. Kesby, Deniz Kirik, Oliver Howes, Darryl Eyles

Original languageEnglish
Article number4294
JournalScientific Reports
Volume11
Issue number1
DOIs
PublishedDec 2021

Bibliographical note

Funding Information: The NHMRC Grant APP1124724 was awarded to DE and OH, and funded aspects of this work. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

An increase in dopamine (DA) synthesis capacity in the dorsal striatum (DS) during the prodromal stage of schizophrenia becomes more pronounced as patients progress to the full disorder. Understanding this progression is critical to intervening in disease course. We developed an animal model—Enhanced Dopamine in Prodromal Schizophrenia (EDiPS)—which uses a genetic construct to increase DA synthesis capacity in the DS of male rats. We assessed pre-pulse inhibition (PPI) and amphetamine (AMPH)-induced locomotion (0.6 mg/kg) in EDiPS animals longitudinally after post-natal day 35 (when the EDiPS construct is administered). We also assessed their response to repeated acute restraint stress. In adult EDiPS animals, we measured baseline and evoked extracellular DA levels, and their stereotyped responses to 5 mg/kg AMPH. AMPH-induced hyperlocomotion was apparent in EDiPS animals 6-weeks after construct administration. There was an overall PPI deficit in EDiPS animals across all timepoints, however the stress response of EDiPS animals was unaltered. Adult EDiPS animals show normal baseline and potassium-evoked DA release in the DS. These findings suggest that key behavioural phenotypes in EDiPS animals show a progressive onset, similar to that demonstrated by patients as they transition to schizophrenia. The EDiPS model could therefore be used to investigate the molecular mechanisms underlying the prodrome of schizophrenia.

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