Prolonged exposure to NMDAR antagonist suppresses inhibitory synaptic transmission in prefrontal cortex

J Neurophysiol. 2008 Aug;100(2):959-65. doi: 10.1152/jn.00079.2008. Epub 2008 Jun 4.

Abstract

Postmortem studies have shown that schizophrenia produces a reduction in the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), a key enzyme for gamma-aminobutyric acid (GABA) synthesis. N-methyl-d-aspartate receptor (NMDAR) antagonists have been extensively used to study schizophrenia because they can induce many aspects of the disease, including the decrease in GAD67. It is generally thought that this reduction in GAD implies a reduction in functional inhibition, but direct evidence had been lacking. We have therefore performed physiological studies in slices of prefrontal cortex taken from rats treated with the NMDAR antagonist ketamine. Both frequency and amplitude of miniature inhibitory postsynaptic currents were reduced. Consistent with a reduction of inhibition, we observed an increase in postsynaptic excitability. The increased excitability is likely to result from disinhibition because miniature excitatory postsynaptic current properties and intrinsic excitability were not changed. Ketamine did not affect inhibition or GAD levels in young rats, indicating a developmental regulation that may be related to the developmental increase in ketamine sensitivity that occurs in humans. Our results show that NMDAR antagonist produces biochemical changes in the GABA system that lead to a functional disinhibition. Such disinhibition would be expected to decrease gamma oscillations, which are reduced in schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Age Factors
  • Animals
  • Dose-Response Relationship, Radiation
  • Electric Stimulation / methods
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Gene Expression Regulation / drug effects
  • Glutamate Decarboxylase / metabolism
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials / drug effects*
  • Ketamine / pharmacology*
  • Male
  • Neural Inhibition / drug effects*
  • Parvalbumins / metabolism
  • Prefrontal Cortex / cytology*
  • Pyramidal Cells / drug effects*
  • Rats
  • Rats, Long-Evans

Substances

  • Excitatory Amino Acid Antagonists
  • Parvalbumins
  • Ketamine
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1