4.0 Article

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

Journal

BEHAVIOURAL PHARMACOLOGY
Volume 32, Issue 5, Pages 404-412

Publisher

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FBP.0000000000000632

Keywords

brain-derived neurotrophic factor; 7; 8-dihydroxyflavone; dopamine; maternal immune activation; polyinosinic-polycytidylic acid; prepulse inhibition; schizophrenia

Funding

  1. National Health and Medical Research Council of Australia

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The study suggests that in offspring of maternal immune activation (MIA), the TrkB agonist 7,8-DHF can reverse PPI deficits caused by dopaminergic stimulation, possibly through the increased expression of BDNF in the frontal cortex. Targeting BDNF signaling may have therapeutic potential for treating certain symptoms of schizophrenia.
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.

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