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

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.

Fig. 1

LSD enhances spread of recurrent network activity in medial prefrontal cortex (mPFC) induced by focal electrical stimulation (stim electrode) (top diagram). Recurrent activity, recorded in mPFC slice by whole cell patch pipette, is depicted as spreading from initial zone (blue oval) to impinge upon a more distant layer V pyramidal cell. Traces below show example of LSD-induced increase in recurrent activity over basal condition; recurrent activity consists of a mix of EPSCs and IPSCs. Downward deflection of baseline reveals a slow inward current or SIC (shaded area) accompanying the recurrent activity. Also note that the fast EPSC is not altered appreciably (provided by G. Aghajanian)

Fig. 2

Autoradiograpy showing overlap between binding at mGlu2/3 receptors (labeled by ³H-SCH354740) and 5-HT_2A/C receptors of the mescaline-like hallucinogen ¹²⁵DOI (top) in mPFC. Traces (lower left) show marked enhancement of basal late evoked slow depolarization by the mescaline-like hallucinogen DOI in a layer V mPFC cell (B2); note synaptic potentials riding upon the wave of depolarization. Subsequent traces show a dose-dependent suppression of the DOI effect by the mGlu2/3 agonist LY354740. Plot (lower right) shows summary dose–response data. Note the late “EPSP” is more sensitive to LY354740 than the early EPSP. Also note that the recordings were in current clamp rather than voltage clamp mode; thus, unlike Figs. 1, 3, and 4, the responses are given in terms of potential rather current—its voltage clamp counterpart. Montage adapted from Marek et al.

Fig. 3

Recurrent activity (and associated SIC) induced by either DOI (upper traces) or the GABA_A antagonist bicuculline (bic) (lower traces) is suppressed by a nanomolar concentration of the D1 dopamine receptor antagonist SKF383393. Note in the superimposed traces that there is no reduction in the fast EPSC. Modified from Lambe and Aghajanian

Fig. 4

Proposed role of astrocytes in the generation of recurrent activity and slow inward currents (SICs). Drawing in upper panel depicts a synapse in which an adjacent astrocyte process slowly releases glutamate (in response to glutamate spillover) onto extrasynaptic NR2B receptors to give rise to glia-to-neuron SICs (adapted from Haydon and Carmignoto 2006). In contrast, the fast neuron-to-neuron response is of much shorter in duration. Traces below illustrate blockade of DOI-induced SICs by SCH79797, a selective antagonist of the astrocytic PAR1 receptor. Note the concomitant suppression of associated recurrent activity. Also note that the fast EPSC is unchanged as indicated by superimposition of the two traces (provided by G. Aghajanian)