Trends in Neurosciences
Volume 27, Issue 11, November 2004, Pages 683-690
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Genes, dopamine and cortical signal-to-noise ratio in schizophrenia

https://doi.org/10.1016/j.tins.2004.08.002Get rights and content

A large body of phenomenological evidence implicates abnormal connectivity of brain macrocircuitry and microcircuitry in schizophrenia. Recent discoveries of susceptibility genes for schizophrenia have zeroed in on the synaptic signaling machinery of cortical microcircuits as fundamental to disease causation and have militated for further revision of the role of dopamine in this illness. Dopamine, long implicated in psychosis and in antipsychotic drug effects, is crucial in optimizing signal-to-noise ratio of local cortical microcircuits. This action of dopamine is achieved principally by D1- and D2-receptor-mediated effects on pyramidal and local circuit neurons, which mediate neuronal excitability and recurrent inhibition and thus contribute to the stability of cortical representations of external and internal stimuli. In schizophrenia, an abnormal cortical dopamine D1/D2 activation ratio – in concert with, and in part related to, altered GABA and glutamate transmission – appears to interfere crucially with this process.

Section snippets

Cortical microcircuit biology in schizophrenia

Evidence of cortical pathology in schizophrenia has emerged from many lines of investigation. Anatomical imaging studies have found gray matter volume deficits in first-episode [4] and chronic [1] schizophrenic patients, as well as before the outbreak of psychosis [5] and in non-psychotic family members [6] – the latter findings suggest a relationship to primary genetic susceptibility. Reductions of gray matter volume, however, appear to be accompanied not by a consistent change in total neuron

The dopamine hypothesis revisited

The hypothesis of increased dopamine signaling in schizophrenia has served for over forty years as the major heuristic framework for understanding the impaired synaptic mechanisms in schizophrenia, and it remains the primary target of pharmacological treatment. As new information about dopamine pharmacology emerged during this period, the hypothesis underwent several revisions. Early versions focused on dopamine metabolism or receptor binding in striatum, primarily because of the dense striatal

Concluding remarks

Functional breakdown in microcircuit neuronal connectivity in schizophrenia might result from multiple molecular mechanisms involved in local circuit dynamics. Dopamine signaling, long considered relevant to symptomatic treatment, appears to be a key factor in mediating cortical SNR and serves as a heuristic model for understanding deficient functional connectivity of local cortical microcircuits. Abnormal decreases in the ratio of D1/D2 signaling – together with other molecular abnormalities

Acknowledgements

We are indebted to several colleagues whose ideas contributed to this paper. In particular, for many valuable discussions and insights we thank Jeremy K. Seamans and Patricio O'Donnell, both of whom also critiqued the manuscript and, most especially, we thank the late Patricia Goldman-Rakic, whose unique work and generosity guided our efforts, and to whose treasured memory we dedicate this paper.

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