title: Impaired GABAergic inhibition in the prefrontal cortex of early postnatal phencyclidine (PCP)-treated rats.
abstract: A compromised γ-aminobutyric acid (GABA)ergic system is hypothesized to be part of the underlying pathophysiology of schizophrenia. N-methyl-D-aspartate (NMDA) receptor hypofunction during neurodevelopment is proposed to disrupt maturation of interneurons causing an impaired GABAergic transmission in adulthood. The present study examines prefrontal GABAergic transmission in adult rats administered with the NMDA receptor channel blocker, phencyclidine (PCP), for 3 days during the second postnatal week. Whole-cell patch-clamp recordings from pyramidal cells in PCP-treated rats showed a 22% reduction in the frequency of miniature inhibitory postsynaptic currents in layer II/III, but not in layer V pyramidal neurons of the prefrontal cortex. Furthermore, early postnatal PCP treatment caused insensitivity toward effects of the GABA transporter 1 (GAT-1) inhibitor, 1,2,5,6-tetrahydro-1-[2-[[(diphenyl-methylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid, and also diminished currents passed by δ-subunit-containing GABAA receptors in layer II/III pyramidal neurons. The observed impairments in GABAergic function are compatible with the alteration of GABAergic markers as well as cognitive dysfunction observed in early postnatal PCP-treated rats and support the hypothesis that PCP administration during neurodevelopment affects the functionality of interneurons in later life.
authors.affiliation: Synaptic Transmission I, H. Lundbeck A/S, 2500 Valby, Denmark Department of Pharmacology and Pharmacotherapy, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Celia
authors.initials: C
authors.lastname: Kjaerby
authors.affiliation: Synaptic Transmission I, H. Lundbeck A/S, 2500 Valby, Denmark Center for Psychiatric Schizophrenia Research, Psychiatric Center Glostrup, 2600 Glostrup, Denmark.
authors.forename: Brian V
authors.initials: BV
authors.lastname: Broberg
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Copenhagen, 2100 Copenhagen, Denmark.
authors.forename: Uffe
authors.initials: U
authors.lastname: Kristiansen
authors.affiliation: Synaptic Transmission I, H. Lundbeck A/S, 2500 Valby, Denmark.
authors.forename: Nils Ole
authors.initials: NO
authors.lastname: Dalby
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009557:Nipecotic Acids / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010622:Phencyclidine / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000254:growth & development* / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology; D011912:Rats, Inbred ACI; D011963:Receptors, GABA-A / Q000378:metabolism; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D009557:Nipecotic Acids; D010091:Oximes; D011724:Pyridazines; D011963:Receptors, GABA-A; C493415:Slc6a1 protein, rat; C078793:NNC 711; D005680:gamma-Aminobutyric Acid; C049853:gabazine; D010622:Phencyclidine
keywords: NMDA receptor antagonist; development; electrophysiology; frontal cortex; interneuron