TrkB agonist 7,8-dihydroxyflavone reverses an induced prepulse inhibition deficit selectively in maternal immune activation offspring: Implications for schizophrenia

Jaehne, Emily J., Chong, Elaine Mei San, Sbisa, Alyssa, Gillespie, Brendan, Hill, Rachel, Gogos, Andrea, and van den Buuse, Maarten (2021) TrkB agonist 7,8-dihydroxyflavone reverses an induced prepulse inhibition deficit selectively in maternal immune activation offspring: Implications for schizophrenia. Behavioural Pharmacology, 32 (5). pp. 404-412.

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Abstract

Reduced brain-derived neurotrophic factor (BDNF) signalling has been implicated in schizophrenia endophenotypes, including deficits in prepulse inhibition (PPI). Maternal immune activation (MIA) is a widely used neurodevelopmental animal model for schizophrenia but it is unclear if BDNF and its receptor, tropomyosin receptor kinase B (TrkB), are involved in PPI regulation in this model. Pregnant Long Evans rats were treated with the viral mimetic, polyinosinic-polycytidylic acid (poly I:C; 4 mg/kg i.v.), and nine male offspring from these dams were compared in adulthood to 11 male Long Evans controls. Offspring underwent PPI testing following injection with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) (10 mg/kg i.p.), with or without the dopamine receptor agonist, apomorphine (APO; 1 mg/kg s.c.), or the dopamine releasing drug, methamphetamine (METH; 2 mg/kg s.c.). Acute administration of APO and METH caused the expected significant reduction of PPI. Acute administration of 7,8-DHF did not alter PPI on its own; however, it significantly reversed the effect of APO on PPI in poly I:C rats, but not in controls. A similar trend was observed in combination with METH. Western blot analysis of frontal cortex revealed significantly increased levels of BDNF protein, but not TrkB or phosphorylated TrkB/TrkB levels, in poly I:C rats. These findings suggest that, selectively in MIA offspring, 7,8-DHF has the ability to reverse PPI deficits caused by dopaminergic stimulation. This effect could be associated with increased BDNF expression in the frontal cortex. These data suggest that targeting BDNF signalling may have therapeutic potential for the treatment of certain symptoms of schizophrenia.

Item ID: 70662
Item Type: Article (Research - C1)
ISSN: 1473-5849
Keywords: 7,8-dihydroxyflavone, brain-derived neurotrophic factor, dopamine, maternal immune activation, polyinosinic-polycytidylic acid, prepulse inhibition, schizophrenia
Copyright Information: Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Funders: National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: NHMRC Career Development Fellowship, NHMRC Senior Research Fellowship
Date Deposited: 10 May 2022 21:25
Downloads: Total: 1
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