Behavioral and Neurochemical Consequences of Cortical Oxidative Stress on Parvalbumin-Interneuron Maturation in Rodent Models of Schizophrenia

Neuropharmacology. 2012 Mar;62(3):1322-31. doi: 10.1016/j.neuropharm.2011.01.049. Epub 2011 Feb 17.

Abstract

Oxidative stress, in response to the activation of the superoxide-producing enzyme Nox2, has been implicated in the schizophrenia-like behavioral dysfunction that develops in animals that were subject to either neonatal NMDA receptor-antagonist treatment or social isolation. In both of these animal models of schizophrenia, an environmental insult occurring during the period of active maturation of the fast-spiking parvalbumin-positive (PV+) interneuronal circuit leads to a diminished expression of parvalbumin in GABA-inhibitory neurons when animals reach adulthood. The loss of PV+ interneurons in animal models had been tentatively attributed to the death of these neurons. However, present results show that for the perinatal NMDA-R antagonist model these interneurons are still alive when animals are 5-6 weeks of age even though they have lost their phenotype and no longer express parvalbumin. Alterations in parvalbumin expression and sensory-evoked gamma-oscillatory activity, regulated by PV+ interneurons, are consistently observed in schizophrenia. We propose that cortical networks consisting of faulty PV+ interneurons interacting with pyramidal neurons may be responsible for the aberrant oscillatory activity observed in schizophrenia. Thus, oxidative stress during the maturation window for PV+ interneurons by alteration of normal brain development, leads to the emergence of schizophrenia-like behavioral dysfunctions when subjects reach early adulthood.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cerebral Cortex / metabolism*
  • Disease Models, Animal*
  • Humans
  • Interneurons / metabolism*
  • Interneurons / pathology
  • Mice
  • Motor Activity / physiology
  • Oxidative Stress*
  • Parvalbumins / metabolism*
  • Rats
  • Rodentia
  • Schizophrenia / metabolism*
  • Schizophrenia / pathology

Substances

  • Parvalbumins