title: Ketamine alters cortical integration of GABAergic interneurons and induces long-term sex-dependent impairments in transgenic Gad67-GFP mice.
abstract: Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, widely used as an anesthetic in neonatal pediatrics, is also an illicit drug named Super K or KitKat consumed by teens and young adults. In the immature brain, despite several studies indicating that NMDA antagonists are neuroprotective against excitotoxic injuries, there is more and more evidence indicating that these molecules exert a deleterious effect by suppressing a trophic function of glutamate. In the present study, we show using Gad67-GFP mice that prenatal exposure to ketamine during a time-window in which GABAergic precursors are migrating results in (i) strong apoptotic death in the ganglionic eminences and along the migratory routes of GABAergic interneurons; (ii) long-term deficits in interneuron density, dendrite numbers and spine morphology; (iii) a sex-dependent deregulation of γ-aminobutyric acid (GABA) levels and GABA transporter expression; (iv) sex-dependent changes in the response to glutamate-induced calcium mobilization; and (v) the long-term sex-dependent behavioral impairment of locomotor activity. In conclusion, using a preclinical approach, the present study shows that ketamine exposure during cortical maturation durably affects the integration of GABAergic interneurons by reducing their survival and differentiation. The resulting molecular, morphological and functional modifications are associated with sex-specific behavioral deficits in adults. In light of the present data, it appears that in humans, ketamine could be deleterious for the development of the brain of preterm neonates and fetuses of addicted pregnant women.
authors.affiliation: ERI28, NeoVasc, Laboratory of Microvascular Endothelium and Neonatal Brain Lesions, Institute of Research for Innovation in Biomedicine, Normandy University, Rouen, France.
authors.forename: C
authors.initials: C
authors.lastname: Aligny
authors.affiliation: ERI28, NeoVasc, Laboratory of Microvascular Endothelium and Neonatal Brain Lesions, Institute of Research for Innovation in Biomedicine, Normandy University, Rouen, France.
authors.forename: C
authors.initials: C
authors.lastname: Roux
authors.affiliation: ERI28, NeoVasc, Laboratory of Microvascular Endothelium and Neonatal Brain Lesions, Institute of Research for Innovation in Biomedicine, Normandy University, Rouen, France.
authors.forename: N
authors.initials: N
authors.lastname: Dourmap
authors.affiliation: ERI28, NeoVasc, Laboratory of Microvascular Endothelium and Neonatal Brain Lesions, Institute of Research for Innovation in Biomedicine, Normandy University, Rouen, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Ramdani
authors.affiliation: Behavioural Analysis Facility, Institute of Research for Innovation in Biomedicine, Normandy University, Rouen, France.
authors.forename: J-C
authors.initials: JC
authors.lastname: Do-Rego
authors.affiliation: ERI28, NeoVasc, Laboratory of Microvascular Endothelium and Neonatal Brain Lesions, Institute of Research for Innovation in Biomedicine, Normandy University, Rouen, France.
authors.forename: S
authors.initials: S
authors.lastname: Jégou
authors.affiliation: ERI28, NeoVasc, Laboratory of Microvascular Endothelium and Neonatal Brain Lesions, Institute of Research for Innovation in Biomedicine, Normandy University, Rouen, France.
authors.forename: P
authors.initials: P
authors.lastname: Leroux
authors.affiliation: ERI28, NeoVasc, Laboratory of Microvascular Endothelium and Neonatal Brain Lesions, Institute of Research for Innovation in Biomedicine, Normandy University, Rouen, France.
authors.forename: I
authors.initials: I
authors.lastname: Leroux-Nicollet
authors.affiliation: 1] ERI28, NeoVasc, Laboratory of Microvascular Endothelium and Neonatal Brain Lesions, Institute of Research for Innovation in Biomedicine, Normandy University, Rouen, France [2] Department of Neonatal Paediatrics and Intensive Care, Rouen University Hospital, Rouen, France.
authors.forename: S
authors.initials: S
authors.lastname: Marret
authors.affiliation: ERI28, NeoVasc, Laboratory of Microvascular Endothelium and Neonatal Brain Lesions, Institute of Research for Innovation in Biomedicine, Normandy University, Rouen, France.
authors.forename: B J
authors.initials: BJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D013287:Illicit Drugs / Q000009:adverse effects / Q000378:metabolism; D007649:Ketamine / Q000009:adverse effects* / Q000378:metabolism; D008124:Locomotion; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D012726:Sexual Behavior, Animal; D013045:Species Specificity; D019966:Substance-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D013287:Illicit Drugs; D018079:Receptors, GABA; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007649:Ketamine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D002118:Calcium