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Corticosterone antagonist or TrkB agonist attenuates schizophrenia-like behavior in a mouse model combining Bdnf-e6
Yanhui Chen1, Shangjin Li1, Tianyi Zhang1
1School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China.
Abstract:
While schizophrenia pathogenesis involves both genetic and environmental factors, their specific combinations remain ill-defined. Here we show that deficiency in promoter VI-driven BDNF expression, combined with early-life adversity, results in schizophrenia-like endo-phenotypes. Promoter VI mutant mice (Bdnf-e6 ), when exposed to postnatal stress including hypoxia or social isolation, exhibited deficits in social interactions, spatial memory, and sensorimotor gating reflected by prepulse inhibition (PPI). Neither early-life stress nor Bdnf-e6 deficiency alone caused these abnormalities. Moreover, postnatal stress increased blood corticosterone levels of wild-type mice, and administration of corticosterone to Bdnf-e6-/- mice without early-life stress also resulted in PPI deficits and social dysfunction. Finally, the PPI deficits in postnatally stressed Bdnf-e6-/- mice were rescued by treatment with the corticosterone antagonist RU-486, or the BDNF mimetic TrkB agonistic antibody. Thus, we have identified a pair of genetic and environmental factors contributing to schizophrenia pathogenesis and providing a potential strategy for therapeutic interventions for schizophrenia.
Insights
Genetic and environmental factors, specifically reduced BDNF and early stress, cause schizophrenia-like behaviors in mice. Therapeutic strategies targeting BDNF and corticosterone show promise for schizophrenia treatment.
Area of Science:
- Neuroscience
- Genetics
- Psychiatry
Background:
- Schizophrenia pathogenesis involves complex interactions between genetic predisposition and environmental triggers.
- The precise interplay between specific genetic factors, such as Brain-Derived Neurotrophic Factor (BDNF) expression, and early-life adversity in schizophrenia remains unclear.
Purpose of the Study:
- To investigate the combined effects of reduced BDNF expression and early-life stress on the development of schizophrenia-like endophenotypes.
- To explore potential therapeutic interventions for schizophrenia by targeting BDNF signaling and stress hormone pathways.
Main Methods:
- Utilized promoter VI mutant mice (Bdnf-e6-/-) and exposed them to early-life stressors (hypoxia, social isolation).
- Assessed behavioral deficits including social interaction, spatial memory, and sensorimotor gating (prepulse inhibition - PPI).
- Measured blood corticosterone levels and evaluated the effects of corticosterone administration, a BDNF mimetic, and a corticosterone antagonist (RU-486).
Main Results:
- Combined early-life stress and Bdnf-e6 deficiency induced schizophrenia-like endophenotypes, including social deficits, memory impairment, and reduced PPI.
- Neither genetic deficiency nor stress alone produced these abnormalities.
- Stress elevated corticosterone levels; corticosterone administration mimicked behavioral deficits, which were reversed by RU-486 or a TrkB agonistic antibody.
Conclusions:
- A specific combination of reduced BDNF signaling and early-life adversity is sufficient to trigger schizophrenia-like phenotypes.
- This study identifies a critical gene-environment interaction in schizophrenia pathogenesis.
- Targeting BDNF pathways and modulating corticosterone offer potential therapeutic avenues for schizophrenia.
