New neurochemical markers for psychosis: a working hypothesis of their operation.
Reelin (Reln) is expressed in specific GABAergic neurons in layer I and II of neocortex, and is secreted into the extracellular matrix where it surrounds dendrites, spines and neurite arborizations, and binds to integrin receptors located on post-synaptic densities of apical dendritic spines. Experiments in rodents (including wild type or reeler heterozygous mice) and non-human primates suggest the Reln secreted in the extracellular matrix of neocortex, via integrin receptors, modulates the function of the adaptor protein DAB1(drosophila disable-gene) homologous product) thereby participating in dynamic processes associated with plasticity changes in dendrites, dendritic spines and their synapses. A local protein synthesis at dendritic spines (ie the activity regulated cytoskeleton associated protein, Arc) probably acts as a signal for plastic modulatory activities in synapses operative in neural group interactions. A research strategy directed toward identifying specific neurochemical markers operative in the etiopathology of psychotic disorders lead to the identification of a downregulation (30-50%) of Reln and glutamic acid decarboxylase 67(GAD67) expression in prefrontal cortex and other brain areas of schizoprenia and bipolar disorder patients with psychosis. These downregulations were not due to neuronal damage, postmortem interval, or antipsychotic medication. The dysfunction of GABAergic interneurons observed in psychotic brains in combination with reduced Reln expression and downregulation of Reln-integrin receptor interaction, may provide an explanation for the reported decrease in neuropile expression including dendritic spine density reduction, in neocortex of schizophrenia patients. This downregulation of neuropile plasticity may be a factor to be considered in the etiology of the disintegration of consciousness, which is one of the primary signs of psychosis.
Guidotti
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Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 60612, USA. aguidotti@psych.uic.edu
Pesold
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Costa
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D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D015816:Cell Adhesion Molecules, Neuronal / Q000032:analysis / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000032:analysis / Q000235:genetics; D005656:Fungal Proteins / Q000032:analysis; D005968:Glutamate Decarboxylase / Q000032:analysis; D006801:Humans; D007527:Isoenzymes / Q000032:analysis; D051379:Mice; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000032:analysis*; D011323:Primates; D011618:Psychotic Disorders / Q000473:pathology* / Q000503:physiopathology*; D000091042:Reelin Protein; D012697:Serine Endopeptidases
D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal; C113062:DAB1 protein, Neurospora crassa; D016326:Extracellular Matrix Proteins; D005656:Fungal Proteins; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2