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Comment by Shoji Tanaka
I appreciate the excellent review by Dr. Abi-Dargham on the current status of the dopamine (DA) hypothesis of schizophrenia. Although it covers many important issues, I here would like to add a new perspective on the dopaminergic modulation of the activity of the prefrontal cortex (PFC) and its relevance to schizophrenia. It is a circuit dynamics perspective.
As Dr. Abi-Dargham reviewed, the relationship between cortical dopaminergic transmission and symptoms of schizophrenia is not yet definitive, even though many studies have suggested hypodopaminergic transmission in the PFC in association with cognitive and negative symptoms. The so-called inverted U-shaped profile of the dependence of working memory performance on the D1 receptor activation level illustrates how the cognitive function declines with the deviation of the DA level in the PFC from the optimum point (Goldman-Rakic et al., 2000). A recent computational study, however, suggests that the PFC circuit is not always stable along the inverted U- shaped curve (Tanaka, 2006).
The stability of the PFC circuit depends on the DA tone in the PFC, and may have more direct links to schizophrenia than the dopaminergic transmission itself. The closed-loop circuitry of the prefronto-mesoprefrontal system (Frankle et al., 2006; Sesack and Carr, 2002) can work as a "regulator" of the PFC activity for working memory if the system is stable (Tanaka, 2006). A conventional stability analysis shows that the closed-loop circuit is indeed stable when the DA level is around the optimum point or higher (Tanaka, 2006). Under hypodopaminergic conditions, in contrast, the system becomes unstable and no longer works as a regulator of the PFC activity. This is because the closed-loop gain of the system varies with the DA level in the PFC, and the switchover from a negative feedback system to a positive feedback system occurs as the cortical DA level decreases. The dysregulation of the PFC activity would be responsible for cognitive deficits in schizophrenia.
Because of the instability of the PFC circuit, an increase in DA releasability in the PFC would cause a "catastrophic jump" in the PFC activity from a very low level to a high level (Tanaka, 2006). And, provided that a hypodopaminergic state of the PFC is relevant to schizophrenia, as reviewed by Dr. Abi-Dargham, this can lead to overactivation of the PFC of patients with schizophrenia during working memory performance. This may be one of the reasons why functional MRI studies of patients with schizophrenia show seemingly inconsistent activation of the PFC (Callicott et al., 2003; Manoach, 2003). Due to the circuit instability, the PFC activity would be intrinsically fluctuating in schizophrenia, which may have implications for understanding the nature of schizophrenia. Although further studies are obviously necessary, the research into the mechanisms of schizophrenia would require a dynamic, rather than a static, point of view.
Callicott JH, Mattay VS, Verchinski BA, Marenco S, Egan MF, Weinberger DR. Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am J Psychiatry. 2003 Dec;160(12):2209-15. Abstract
Frankle WG, Laruelle M, Haber SN. Prefrontal cortical projections to the midbrain in primates: evidence for a sparse connection. Neuropsychopharmacology. 2006 Aug;31(8):1627-36. Abstract
Goldman-Rakic PS, Muly EC 3rd, Williams GV. D(1) receptors in prefrontal cells and circuits. Brain Res Brain Res Rev. 2000 Mar;31(2-3):295-301. Review. No abstract available. Abstract
Manoach DS. Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res. 2003 Apr 1;60(2-3):285-98. Review. Abstract
Sesack SR, Carr DB. Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia. Physiol Behav. 2002 Dec;77(4-5):513-7. Review. Abstract
Tanaka S. Dopaminergic control of working memory and its relevance to schizophrenia: a circuit dynamics perspective. Neuroscience. 2006 Apr 28;139(1):153-71. Epub 2005 Dec 1. Review. Abstract