Evidence for a compromised dorsolateral prefrontal cortical parallel circuit in schizophrenia

Evidence is reviewed that one of the cognitive-affective parallel circuits in the brain, the dorsolateral prefrontal circuit, is compromised at the level of anatomical, neuropathological and transmitter-related molecules in a subgroup of schizophrenic patients. The dorsolateral prefrontal cortex (DLPFC) comprises a key structure in this circuit. Data supporting a compromised DLPFC includes cognitive deficits, decreased regional metabolism and blood flow activation; disruption of cortical subplate activity (inferred from maldistribution of neurons from the cortical subplate which are required for the orderly neuronal migration during the second trimester and for connectivity of the thalamocortical neurons); decrease in major components of the cortical inhibitory neurotransmitter system; and alterations in the molecules critical for NMDA-receptor mediated neural transmission. Thus a great deal of evidence accumulated over the last decade has definitively implicated the dorsolateral prefrontal cortex in the pathophysiology of schizophrenia. Emerging data also confirms neuropathology in the mediodorsal nucleus of the thalamus that projects to the DLPFC. There is currently a consensus that schizophrenia involves epigenetic factors interacting with genetic information in the cells to produce abnormal molecules which when they are associated with abnormal circuits such as the DLPFC, may result in abnormal behavior. Thus, abnormal cortical connections and or altered neurotransmitter related molecules in the DLPFC could explain some of the prominent frontal cognitive disruptions seen in schizophrenia.