@article{4b96597899ee454abccae8698b2983ba,
title = "Depolarizing GABAA current in the prefrontal cortex is linked with cognitive impairment in a mouse model relevant for schizophrenia",
abstract = "Cognitive impairment in schizophrenia (CIAS) is the most critical predictor of functional outcome. Limited understanding of the cellular mechanisms of CIAS hampers development of more effective treatments. We found that in subchronic phencyclidine (scPCP)–treated mice, an animal model that mimics CIAS, the reversal potential of GABAA currents in pyramidal neurons of the infralimbic prefrontal cortex (ILC) shifts from hyperpolarizing to depolarizing, the result of increased expression of the chloride transporter NKCC1. Further, we found that in scPCP mice, the NKCC1 antagonist bumetanide normalizes GABAA current polarity ex vivo and improves performance in multiple cognitive tasks in vivo. This behavioral effect was mimicked by selective, bilateral, NKCC1 knockdown in the ILC. Thus, we show that depolarizing GABAA currents in the ILC contributes to cognitive impairments in scPCP mice and suggest that bumetanide, an FDA-approved drug, has potential to treat or prevent CIAS and other components of the schizophrenia syndrome.",
author = "Kim, {Haram R.} and Lakshmi Rajagopal and Meltzer, {Herbert Y.} and Marco Martina",
note = "Funding Information: We are grateful to G. Sekerkov? for optimization of the in situ hybridization protocols, to M. Huang for implanting cannulas for intracortical drug infusions, to J. Do for virus injections, and to P. Penzes and G. Maccaferri for critical reading of the manuscript. Funding: This work was supported by NIH grants DA044121 and NS112292d (to M.M.), MH109466 (to H.Y.M.), and by a donation from the Weisman family (to H.Y.M.). H.Y.M. also discloses grant support from Janssen Pharmaceuticals, Allergan, Eli Lilly, Lundbeck, Neurocrine, Takeda, Sumitomo Dainippon, and Sunovion. Author contributions: H.R.K. performed the electrophysiological recordings and analysis, the in situ hybridization, designed the knockdown experiments, and provided critical readings of the manuscript. L.R. performed the PCP/vehicle injections and the behavioral tests and data analysis. H.Y.M. developed the project, designed the behavioral experiments, and cowrote the manusrcipt. M.M. developed the project, designed the patch clamp, in situ hybridization and the knockdown experiments, and wrote the manuscript. Competing interests: M.M. and H.Y.M. are inventors on a patent application related to this work filed by INVO, METHODS FOR TREATING PSYCHIATRIC DISEASES AND DISORDERS AND THE SYMPTOMS THEREOF IN A SUBJECT BY ADMINISTERING AN ANTAGONIST OF THE NA+-K+-2CL-CATION-CHLORIDE COTRANSPORTER ISOFORM 1 (NKCC1), with filing number 16/915,746. The other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved.",
year = "2021",
month = mar,
doi = "10.1126/sciadv.aba5032",
language = "English (US)",
volume = "7",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "14",
}