Modeling "psychosis" in vitro by inducing disordered neuronal network activity in cortical brain slices

Psychopharmacology (Berl). 2009 Nov;206(4):575-85. doi: 10.1007/s00213-009-1484-9. Epub 2009 Feb 25.

Abstract

Introduction: Dysregulation of neuronal networks has been suggested to underlie the cognitive and perceptual abnormalities observed schizophrenia.

Discussions: An in vitro model of psychosis is proposed based on the two different approaches to cause aberrant network activity in layer V pyramidal cells of prefrontal brain slices: (1) psychedelic hallucinogens such as lysergic acid diethylamide and (2) minimal GABA(A) receptor antagonism, modeling the GABA interneuron deficit in schizophrenia. A test of this model would be to determine if drugs that normalize aberrant networks in brain slices have efficacy in the treatment of schizophrenia. Selective agonists of glutamate mGlu2/3 metabotropic receptors, which are highly effective in suppressing aberrant network activity in slices, are the most advanced toward reaching that clinical endpoint. In accord with the model, a recent phase II clinical trial shows that an mGlu2/3 receptor agonist is equivalent in efficacy to a standard antipsychotic drug for both negative and positive symptoms in schizophrenic patients, but without the usual side effects. D1/5 dopamine receptor agonists are also effective in normalizing aberrant network activity induced by both hallucinogens and minimal GABA(A) antagonism; clinical efficacy remains to be determined. A general model of network regulation is presented, involving astrocytes, GABA interneurons, and glutamatergic pyramidal cells, revealing a wide range of potential sites hitherto not considered as therapeutic targets.

Publication types

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

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Clinical Trials, Phase II as Topic
  • Drug Delivery Systems
  • Humans
  • Models, Biological
  • Nerve Net / physiopathology
  • Prefrontal Cortex / physiopathology*
  • Psychotic Disorders / etiology
  • Psychotic Disorders / physiopathology*
  • Schizophrenia / etiology
  • Schizophrenia / physiopathology*

Substances

  • Antipsychotic Agents