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

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.

Adolescent THC Treatment Does Not Potentiate the Behavioral Effects in Adulthood of Maternal Immune Activation

“…In this study, there were no differences in PPI performance following either prenatal poly(I:C) or adolescent THC treatment. Although other groups have reported PPI deficits in rodents treated with prenatal poly(I:C) [ 11 , 23 ], these effects have not been universally demonstrated [ 24 , 25 ]. The origin of breeders [ 26 ] and the timing and dosing of poly(I:C) [ 19 ] have been found to affect PPI response.…”

7,8-Dihydroxyflavone is a direct inhibitor of pyridoxal phosphatase

“…The discovery of 7,8-DHF as a direct PDXP inhibitor was unexpected. Interestingly, numerous in vivo studies have reported the effectiveness of 7,8-DHF in brain disorder models, including rodent models of Alzheimer's disease (50)(51)(52)(53)(54)(55)(56)(57), depression (58)(59)(60)(61)(62)(63), schizophrenia (64)(65)(66)(67)(68), epilepsy (69,70) and autism (71)(72)(73)(74). Although PLP deficiency is thought to contribute to the respective human conditions (3,75,76), PLP-dependent processes have not yet been considered in the context of 7,8-DHF-induced effects.…”

Interaction of Brain-Derived Neurotrophic Factor with the Effects of Chronic Methamphetamine on Prepulse Inhibition in Mice Is Independent of Dopamine D3 Receptors

“…Treatments aimed at stimulation of the BDNF receptor, tropomyosin receptor-kinase B (TrkB), may prove clinically beneficial in counteracting the effects of METH, at least on PPI, and this may extend to psychosis and schizophrenia more generally. Indeed, recently, we showed that treatment with a TrkB receptor agonist could counteract PPI deficits in a maternal immune activation model of psychosis [ 73 ]. Moreover, in other psychosis and schizophrenia models, TrkB receptor activation has also shown promising results [ 74 , 75 ].…”