Abstract
Psychiatric disorders represent a heterogeneous class of multifactorial mental diseases whose origin entails a pathogenic integration of genetic and environmental influences. Incidence of these pathologies is dangerously high, as more than 20% of the Western population is affected. Despite the diverse origins of specific molecular dysfunctions, these pathologies entail disruption of fine synaptic regulation, which is fundamental to behavioral adaptation to the environment. The synapses, as functional units of cognition, represent major evolutionary targets. Consistently, fine synaptic tuning occurs at several levels, involving a novel class of molecular regulators known as long non-coding RNAs (lncRNAs). Non-coding RNAs operate mainly in mammals as epigenetic modifiers and enhancers of proteome diversity. The prominent evolutionary expansion of the gene number of lncRNAs in mammals, particularly in primates and humans, and their preferential neuronal expression does represent a driving force that enhanced the layering of synaptic control mechanisms. In the last few years, remarkable alterations of the expression of lncRNAs have been reported in psychiatric conditions such as schizophrenia, autism, and depression, suggesting unprecedented mechanistic insights into disruption of fine synaptic tuning underlying severe behavioral manifestations of psychosis. In this review, we integrate literature data from rodent pathological models and human evidence that proposes the biology of lncRNAs as a promising field of neuropsychiatric investigation.
Highlights
Psychiatric disorders represent a heterogeneous class of multifactorial mental diseases whose origin entails a pathogenic integration of genetic and environmental influences
RNA sequence experiments have shown that the expression of long non-coding RNAs (lncRNAs) is lower and more tissue- and differentiation-stage-specific when compared to the expression of protein-coding genes, suggesting that they may have a role in fine modulation of cell fate and identity, providing a fundamental contribution to the formation and functioning of tissues and organs [55]
We strongly believe that the role of lncRNAs in neuroplasticity modulation endows many post-mortem transcriptional studies with a novel role of interpretation involving at least those lncRNAs species that undergo activity-induced modulation
Summary
From the genetic point of view, remarkable convergence has recently been observed within multiple psychiatric disorders, indicating that similar molecular pathways are involved in different forms of mental illness, providing a functional perspective on the above-mentioned overlapping symptoms [13,14,15,16] One of these studies took advantage of exome sequencing analyses, which were able to unveil how the same genes and pathways are preferential targets of de novo mutations within patients of three different disorders—ASD, SCZ, and ID [13]. Many recent studies based on RNA sequence analyses have highlighted transcriptional deregulation of long non-coding RNAs (lncRNAs) in the post-mortem brains of psychiatric patients This evidence is consistent with recent discoveries, showing that many mutations linked to neuropsychiatric disorders fall into non-coding regions of the genome. We provide a brief description of three known endophenotypes with established roles in neuropsychiatric disorders, whose potential lncRNA-dependent regulation could reveal remarkable cues for pathomechanisms, and treatment of mental illness
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