Dorsolateral Prefrontal Cortical Parallel Circuit in Schizophrenia: Postmortem Abnormalities

  • Blynn G. Bunney
  • William E. Bunney
  • Richard Stein
  • Steven G. Potkin
Part of the Neurobiological Foundation of Aberrant Behaviors book series (NFAB, volume 4)


Emerging evidence from postmortem studies in schizophrenics implicate disturbances in the dorsolateral prefrontal parallel circuit, specifically in the dorsolateral prefrontal cortex (DLPFC) and mediodorsal nucleus (MD) of the thalamus. Cognitive deficits in schizophrenia include impairments in working memory that are accompanied by test-related decreases in DLPFC activation. The DLPFC is part of the dorsolateral prefrontal cortical parallel circuit, one of three cognitive-affective circuitries. Postmortem evidence for abnormalities in the DLPFC of schizophrenics include abnormal cell settling patterns of interstitial neurons in the white matter, reductions in GAD mRNA, and decreases in γ-2 mRNA of the γ-2 GABA-A receptor subunit as compared to matched controls. The DLPFC has substantial projections to the MD nucleus. Studies in schizophrenics reveal dramatic reductions in neuronal number of the MD with evidence of defects in the MD thalamic subnuclei (i.e., densocellular and parvocellular subnuclei) that project to the DLPFC. Some neuropathological abnormalities in the DLPFC and MD nucleus of schizophrenics could be attributed to disturbances in early cortical development. The neurodevelopmental hypothesis of schizophrenia is supported by the finding that three populations of cortical subplate markers (nicotinamide-adenine dinucleotide phosphate diaphorase, NADPH-d, microtubular-associated protein-2, MAP-2 and a monoclonal antibody that represents a non-phosphorylated neurofilament protein, SMI-32, a 160–200kDA protein), are abnormally distributed in the interstitial white matter of the DLPFC in patients. Disturbances in early neurodevelopment could occur during a period of genetic/environmental vulnerability, most likely in the second trimester, when large numbers of neurons are migrating from the ventricular zone to their target destinations in the cortex. These disturbances might be reflected in abnormal functioning of neuronal circuitries such as the dorsolateral prefrontal parallel circuit containing the DLPFC and MD nucleus of the thalamus.

The dorsola teral prefrontal cortical circuit is one of three parallel circuits in the brain that relates to cognitive-affective function. Figure 1 represents an adaptation of this circuit described by Alexander, DeLong and Strick (1986) and includes the dorsolateral prefrontal cortex (DLPFC), the dorsolateral caudate nucleus of the striatum, the lateral dorsal medial nucleus in globus pallidus, the posterolateral nucleus of the substantia nigra, and the mediodorsal nucleus of the thalamus. Using a neurotropic virus tracer capable of labeling multisynaptic neuronal connections (McIntyre B-strain of herpes simplex virus type 1—HSV1), Middleton and Strick (2000) identified areas 9 and 46 (two nuclei within the DLPFC) as receiving input from the substantia nigra and globus pallidus via the mediodorsal nucleus of the thalamus. The thalamus is composed of eleven identified nuclei. One of these, the mediodorsal nucleus, projects to the DLPFC. Within the mediodorsal nucleus, three subnuclei have been identified. These include the magnocellular, parvocellular and the densocellular nuclei. The latter two subnuclei project to the middle layers of the DLPFC. Specific cellular and molecular abnormalities in the subnuclei and the DLPFC in schizophrenic brains are reviewed below. These abnormalities clearly could be associated with some of the prominent prefrontal cognitive deficits observed in schizophrenia. To date, as reviewed below, an impressive body of research implicates the DLPFC.


Prefrontal Cortex Wisconsin Card Sort Test GABAA Receptor Subunit Mediodorsal Nucleus DLPFC Activation 
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© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Blynn G. Bunney
  • William E. Bunney
  • Richard Stein
  • Steven G. Potkin

There are no affiliations available

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