Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages prevents schizophrenia-relevant phenotypes in adult offspring after maternal immune activation: a role of TrkB signaling

• Published in: European archives of psychiatry and clinical neuroscience Vol. 272; no. 4; pp. 693 - 701
• Main Authors: Tan, Yunfei, Fujita, Yuko, Pu, Yaoyu, Chang, Lijia, Qu, Youge, Wang, Xinming, Hashimoto, Kenji
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2022; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult Children; Animals; Antidepressants; Child psychopathology; Cognitive ability; Dendritic spines; Dentate gyrus; Disease Models, Animal; Etiology; Female; Genetic aspects; Hippocampus; Humans; Immune response; Immunoreactivity; Ketamine; Ketamine - pharmacology; Medicine; Medicine & Public Health; Membrane Glycoproteins - metabolism; Mental disorders; Missing in action; Neurosciences; Offspring; Original Paper; Parvalbumin; Phenotype; Phenotypes; Poly I-C - pharmacology; Polyinosinic:polycytidylic acid; Prefrontal cortex; Pregnancy; Pregnant women; Prenatal experience; Prenatal exposure; Psychiatry; Psychosis; Psychotic Disorders; Receptor, trkB - metabolism; Schizophrenia; Schizophrenia - prevention & control; Teenagers; TrkB receptors; Psychosis; Prevention; (; TrkB; ketamine; Cognitive deficits; (R)-ketamine
• ISSN: 0940-1334; 1433-8491; 1433-8491
• DOI: 10.1007/s00406-021-01365-6

Maternal immune activation (MIA) plays a role in the etiology of schizophrenia. MIA by prenatal exposure of polyinosinic:polycytidylic acid [poly(I:C)] in rodents caused behavioral and neurobiological changes relevant to schizophrenia in adult offspring. We investigated whether the novel antidepressant ( R )-ketamine could prevent the development of psychosis-like phenotypes in adult offspring after MIA. We examined the effects of ( R )-ketamine (10 mg/kg/day, twice weekly for 4 weeks) during juvenile and adolescent stages (P28–P56) on the development of cognitive deficits, loss of parvalbumin (PV)-immunoreactivity in the medial prefrontal cortex (mPFC), and decreased dendritic spine density in the mPFC and hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, we examined the role of TrkB in the prophylactic effects of ( R )-ketamine. Repeated intermittent administration of ( R )-ketamine during juvenile and adolescent stages significantly blocked the development of cognitive deficits, reduced PV-immunoreactivity in the prelimbic (PrL) of mPFC, and decreased dendritic spine density in the PrL of mPFC, CA3 and dentate gyrus of the hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, pretreatment with ANA-12 (TrkB antagonist: twice weekly for 4 weeks) significantly blocked the beneficial effects of ( R )-ketamine on cognitive deficits of adult offspring after prenatal poly(I:C) exposure. These data suggest that repeated intermittent administration of ( R )-ketamine during juvenile and adolescent stages could prevent the development of psychosis in adult offspring after MIA. Therefore, ( R )-ketamine would be a potential prophylactic drug for young subjects with high-risk for psychosis.