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

An in vitro model of psychosis is proposed based on two approaches that cause aberrant network activity in layer V pyramidal cells of prefrontal brain slices: psychedelic hallucinogens and minimal GABA(A) receptor antagonism, which models the GABA interneuron deficit in schizophrenia. Selective agonists of glutamate mGlu2/3 metabotropic receptors are highly effective in suppressing this aberrant activity. 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, without the usual side effects. D1/5 dopamine receptor agonists also normalize aberrant network activity, but clinical efficacy remains to be determined.

Study at a glance

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.