Trends in Neurosciences
Genes, dopamine and cortical signal-to-noise ratio in schizophrenia
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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