Adolescent Stress-Induced Ventral Hippocampus Redox Dysregulation Underlies Behavioral Deficits and Excitatory/Inhibitory Imbalance Related to Schizophrenia

Author:

Santos-Silva Thamyris1ORCID,Lopes Caio Fábio Baeta2,Hazar Ülgen Doğukan3,Guimarães Danielle A1,Guimarães Francisco S1,Alberici Luciane Carla2,Sandi Carmen3ORCID,Gomes Felipe V1ORCID

Affiliation:

1. Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto , Brazil

2. Department of Biomolecular Sciences, Ribeirão Preto Pharmaceutical Sciences School, University of São Paulo , Ribeirão Preto , Brazil

3. Brain Mind Institute, École Polytechnique Fédérale de Lausanne , Lausanne , Switzerland

Abstract

Abstract Background and Hypothesis Redox dysregulation has been proposed as a convergent point of childhood trauma and the emergence of psychiatric disorders, such as schizophrenia (SCZ). A critical region particularly vulnerable to environmental insults during adolescence is the ventral hippocampus (vHip). However, the impact of severe stress on vHip redox states and their functional consequences, including behavioral and electrophysiological changes related to SCZ, are not entirely understood. Study Design After exposing adolescent animals to physical stress (postnatal day, PND31–40), we explored social and cognitive behaviors (PND47–49), the basal activity of pyramidal glutamate neurons, the number of parvalbumin (PV) interneurons, and the transcriptomic signature of the vHip (PND51). We also evaluated the impact of stress on the redox system, including mitochondrial respiratory function, reactive oxygen species (ROS) production, and glutathione (GSH) levels in the vHip and serum. Study Results Adolescent-stressed animals exhibited loss of sociability, cognitive impairment, and vHip excitatory/inhibitory (E/I) imbalance. Genome-wide transcriptional profiling unveiled the impact of stress on redox system- and synaptic-related genes. Stress impacted mitochondrial respiratory function and changes in ROS levels in the vHip. GSH and glutathione disulfide (GSSG) levels were elevated in the serum of stressed animals, while GSSG was also increased in the vHip and negatively correlated with sociability. Additionally, PV interneuron deficits in the vHip caused by adolescent stress were associated with oxidative stress. Conclusions Our results highlight the negative impact of adolescent stress on vHip redox regulation and mitochondrial function, which are partially associated with E/I imbalance and behavioral abnormalities related to SCZ.

Funder

São Paulo Research Foundation

International Brain Research Organization

Coordination for the Improvement of Higher Education Personnel—Brazil

CAPES

Swiss National Science Foundation

EPFL

Publisher

Oxford University Press (OUP)

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