Impaired GABAergic inhibition in the prefrontal cortex of early postnatal phencyclidine (PCP)-treated rats

Cereb Cortex. 2014 Sep;24(9):2522-32. doi: 10.1093/cercor/bht109. Epub 2013 Apr 23.

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.

Keywords: NMDA receptor antagonist; development; electrophysiology; frontal cortex; interneuron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Electric Stimulation
  • Excitatory Amino Acid Antagonists / toxicity*
  • GABA Antagonists / pharmacology
  • GABA Plasma Membrane Transport Proteins / metabolism
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology
  • Interneurons / drug effects
  • Interneurons / physiology
  • Miniature Postsynaptic Potentials / drug effects
  • Miniature Postsynaptic Potentials / physiology
  • Nipecotic Acids / pharmacology
  • Oximes / pharmacology
  • Patch-Clamp Techniques
  • Phencyclidine / toxicity*
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / growth & development*
  • Prefrontal Cortex / physiology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / growth & development
  • Pyramidal Cells / physiology
  • Pyridazines / pharmacology
  • Rats, Inbred ACI
  • Receptors, GABA-A / metabolism
  • Tissue Culture Techniques
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Excitatory Amino Acid Antagonists
  • GABA Antagonists
  • GABA Plasma Membrane Transport Proteins
  • Nipecotic Acids
  • Oximes
  • Pyridazines
  • Receptors, GABA-A
  • Slc6a1 protein, rat
  • NNC 711
  • gamma-Aminobutyric Acid
  • gabazine
  • Phencyclidine