Interneuron hypomyelination is associated with cognitive inflexibility in a rat model of schizophrenia

• Published in: Nature communications 2020-05, Vol.11 (1), p.2329-2329, Article 2329
• Main Authors: Maas, Dorien A., Eijsink, Vivian D., Spoelder, Marcia, van Hulten, Josephus A., De Weerd, Peter, Homberg, Judith R., Vallès, Astrid, Nait-Oumesmar, Brahim, Martens, Gerard J. M.
• Format: Article
• Language: English
• Subjects: 13/51; 14/28; 14/63; 38/88; 631/378/1689/1799; 631/378/2596/1705; 64; 64/86; 82/80; Adolescents; Animals; Apomorphine; Axons; Axons - metabolism; Axons - ultrastructure; Cell Lineage; Cognition - physiology; Cognitive ability; Disease Models, Animal; Enrichment; GABAergic Neurons - metabolism; Gene expression; Gene Expression Regulation; Humanities and Social Sciences; Interneurons; Interneurons - pathology; Interneurons - ultrastructure; Learning; Life Sciences; Mental disorders; multidisciplinary; Myelin; Myelin Sheath - pathology; Myelin Sheath - ultrastructure; Myelination; Neurons and Cognition; Oligodendrocytes; Oligodendroglia - pathology; Parvalbumin; Parvalbumins - metabolism; Phenotypes; Prefrontal cortex; Prefrontal Cortex - physiopathology; Rats, Wistar; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Schizophrenia; Schizophrenia - pathology; Schizophrenia - physiopathology; Science; Science (multidisciplinary); γ-Aminobutyric acid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16218-4

Impaired cognitive functioning is a core feature of schizophrenia, and is hypothesized to be due to myelination as well as interneuron defects during adolescent prefrontal cortex (PFC) development. Here we report that in the apomorphine-susceptible (APO-SUS) rat model, which has schizophrenia-like features, a myelination defect occurred specifically in parvalbumin interneurons. The adult rats displayed medial PFC (mPFC)-dependent cognitive inflexibility, and a reduced number of mature oligodendrocytes and myelinated parvalbumin inhibitory axons in the mPFC. In the developing mPFC, we observed decreased myelin-related gene expression that persisted into adulthood. Environmental enrichment applied during adolescence restored parvalbumin interneuron hypomyelination as well as cognitive inflexibility. Collectively, these findings highlight that impairment of parvalbumin interneuron myelination is related to schizophrenia-relevant cognitive deficits. Dysfunction of GABAergic neurons in the prefrontal cortex has been reported in schizophrenia. Here, the authors use the apomorphine-susceptible rat, which displays some schizophrenia-like behaviors, and show that interneurons in the medial prefrontal cortex are hypomyelinated, which may contribute to this behavioral phenotype.