Three independent lines of evidence suggest retinoids as causal to schizophrenia

Abstract

Retinoid dysregulation may be an important factor in the etiology of schizophrenia. This hypothesis is supported by three independent lines of evidence that triangulate on retinoid involvement in schizophrenia: (i) congenital anomalies similar to those caused by retinoid dysfunction are found in schizophrenics and their relatives; (ii) those loci that have been suggestively linked to schizophrenia are also the loci of the genes of the retinoid cascade (convergent loci); and (iii) the transcriptional activation of the dopamine D2 receptor and numerous schizophrenia candidate genes is regulated by retinoic acid. These findings suggest a close causal relationship between retinoids and the underlying pathophysiological defects in schizophrenia. This leads to specific strategies for linkage analyses in schizophrenia. In view of the heterodimeric nature of the retinoid nuclear receptor transcription factors, e.g., retinoid X receptor ␤ at chromosome 6p21.3 and retinoic acid receptor ␤ at 3p24.3, two-locus linkage models incorporating genes of the retinoid cascade and their heterodimeric partners, e.g., peroxisome proliferatoractivated receptor ␣ at chromosome 22q12-q13 or nuclearrelated receptor 1 at chromosome 2q22-q23, are proposed. New treatment modalities using retinoid analogs to alter the downstream expression of the dopamine receptors and other genes that are targets of retinoid regulation, and that are thought to be involved in schizophrenia, are suggested.

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

“…Other functions associated with the nucleus accumbens and the StDM (more limbic areas) may also be associated with an NGFI-B activity, since similar alterations of haloperidolinduced biochemical effects are observed in those structures in the NGFI-B-deficient mice (Table 1). The role of retinoids in the development of the CNS is well known (Maden, 2002) and molecular and genetic approaches have previously suggested an association of retinoid genetic markers and vulnerability to schizophrenia (Goodman, 1998;LaMantia, 1999). The present data indicate, for the first time, that retinoids (a vitamin A derivative and an o-3 PUFA) and nuclear receptors may be involved in neuroleptic-mediated actions in fully developed animals.…”

Retinoid Hyposignaling Contributes to Aging-Related Decline in Hippocampal Function in Short-Term/Working Memory Organization and Long-Term Declarative Memory Encoding in Mice

“…Furthermore, dysfunction of retinoid signaling pathway has been hypothesized to be involved in human neurodevelopmental pathologies such as schizophrenia or late-onset Alzheimer's disease (for review, Goodman, 1998Goodman, , 2006Goodman and Pardee, 2003;Palha and Goodman, 2006).…”

Novel Treatments of Psychosis

“…Goodman first presented the retinoid dysregulation hypothesis by proposing three lines of evidence implicating its involvement in the pathogenesis of schizophrenia [44]. First, toxicity or deficiency of retinoic acid causes developmental abnormalities.…”

“…Second, genetic loci that are associated with schizophrenia contain genes in the retinoid cascade. Third, retinoic acid regulates the transcriptional activation of the D 2 receptor, the target of current antipsychotic medications [44].…”