A Model of microcircuitry underlying the NMDA receptor hypofunction hypothesis of schizophrenia. (a) Under normal conditions, activation of NMDA receptors localized on GABAergic projection neurons (as shown in orange) in subcortical regions, such as the nucleus accumbens, provides inhibitory control on excitatory glutamatergic thalamocortical neurons (as shown in green) that project to pyramidal neurons in the PFC. (b) Hypofunction or blockade of these NMDA receptors on midbrain inhibitory GABAergic neurons, which are normally under excitatory control from glutamatergic afferents, results in decreased excitation of GABAergic inhibitory neurons. (c) This decreased excitation of GABAergic inhibitory neurons leads to disinhibition of thalamocortical glutamatergic neurons that normally provide excitatory input to pyramidal neurons in the PFC. (d) This disinhibition of glutamatergic neurons in the thalamus results in an enhanced release of glutamate, excessive activation of non-NMDA glutamate receptors, and enhanced excitability in postsynaptic structures in the PFC, including pyramidal neurons. mGluR5 and mGluR2/3 receptors are expressed in key regions for the potential modulation of this altered circuitry.