Abstract
A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.
Highlights
A single locus genetic disorder, fragile X syndrome (FXS), the leading inherited cause of intellectual disability (ID) and monogenic syndromic form of autism spectrum disorder (ASD), remains incompletely understood at the mechanistic level
Since the identification of FMR1 as the X-linked gene affected in FXS (Warren et al, 1987; Oberlé et al, 1991; Verkerk et al, 1991; Vincent et al, 1991), significant research efforts have focused on FMRP, the protein encoded by FMR1 (Ashley et al, 1993)
We explore disrupted nitric oxide (NO) signaling as a new candidate mechanism of FXS centered in the developing neocortex
Summary
A single locus genetic disorder, fragile X syndrome (FXS), the leading inherited cause of intellectual disability (ID) and monogenic syndromic form of autism spectrum disorder (ASD), remains incompletely understood at the mechanistic level. We assess disrupted NO signaling as a candidate mechanism underlying FXS, focusing on the highly specific spatiotemporal expression pattern of NOS1 in the fetal human neocortex and the potential neurobiological contribution of disrupted NO signaling to FXS and other neurodevelopmental disorders.
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