Recent studies have found a high genetic similarity of the psychiatric diseases schizophrenia and bipolar disorder, whose disease-specific changes in brain cells show an overlap of more than 70 percent.
These changes affect gene expression, i.e., transcription of genes for the purpose of translation into functional proteins.
A collaborative study carried out by the Institute of Pharmacology and Clinical Pharmacy at Goethe University (Professor Jochen Klein) and the Institute of Neurosciences at the Hebrew University of Jerusalem (Professor Hermona Soreq) now shows sex-specific biases in these changes, as well as in cellular control mechanisms based on endogenous short ribonucleic acid (RNA) chains.
The scientists identified an important role of microRNAs, a special group of these small RNA molecules, known for their extensive control of gene expression in all human cells. T
argeting of a gene by one of these microRNAs can lead to a significant restriction of its expression.
“The main problem is the enormous variety of possible combinations,” says Sebastian Lobentanzer, lead author of the article published in the journal Cell Reports.
“The human expresses about 2,500 of these microRNAs, and a single one can influence hundreds, maybe even thousands of genes.”
For this reason, the researchers investigated gene expression in patient brains as well as human cultured nerve cells with a combination of RNA sequencing and bioinformatics.
They found a difference in the expression of immune-related genes between men and women, especially with regard to cytokines, the messenger substances of immune cells.
Upon exposition of the cultured male and female neuronal cells to some of these cytokines, the researchers found a transformation of nerve cells into to cholinergic neurons, defined by their use of the neurotransmitter “acetylcholine”.
The illustration shows a network of 212 microRNAs and their 12,495 targeted genes, deconstructed into four fields according to their sex-specific changes The image is credited to Sebastian Lobentanzer.
By sequencing the microRNAs at several time points during this process, the scientists were able to paint a detailed picture of the microRNA interface between the immune and neuronal systems.
They identified the involvement of 17 partially sex-dependent families of microRNAs and generated an extensive network of 12,495 regulated genes.
Using a multi-stage selection process, the most influential of these microRNA families were identified and confirmed in dedicated experiments.
This led to the identification of the two sex-specifically expressed families mir-10 and mir-199 as interface between cytokines and cholinergic functions.
Psychiatric diseases are an important field for new therapeutic approaches because of their high genetic complexity and their inaccessibility to conventional forms of therapy.
On the one hand, the current study demonstrates molecular parallels to the long-observed but previously unexplained clinical differences between disease-affected men and women
On the other hand, mechanisms on the basis of small RNA molecules could open up new avenues by influencing a large number of disease-relevant genes – a promising approach in the search for alternatives to traditional antipsychotic drugs.
“Studies such as ours, which enable a comprehensive representation of microRNA interactions, are the first step on the path to developing new therapeutic substances,” says Lobentanzer.
Schizophrenia and bipolar disorder both have their peak onset in early adulthood. It has been argued for some time that schizophrenia arises as a result of pathological changes occurring during early neurodevelopment1–3.
One influential hypothesis is that at least some of the aetiological events occur during prenatal brain development, but their effects remain latent and are only expressed later as symptoms in the context of brain maturation1,4.
The importance of prenatal neurodevelopment in risk for schizophrenia is supported by epidemiological evidence showing that prenatal and perinatal events such as infection, famine and obstetric complications can increase risk for the disorder, and by the observation that children with subtle neurological, cognitive and behavioural impairments are at enhanced risk for later developing the condition3,6–8.
In general, fewer epidemiological studies have examined associations between prenatal/perinatal events such as maternal infection and obstetric complications and risk for later bipolar disorder9.
Furthermore, there is not strong evidence that individuals who later develop bipolar disorder had poorer premorbid cognitive functioning and social adjustment or increased rates of subtle neurological symptoms7,16.
There has also been interest in the potential role of developmental events occurring postnatally during childhood and adolescence in the development of adult onset psychiatric conditions such as schizophrenia and bipolar disorder5,7,17.
It is well established that extensive neuronal maturation occurs across childhood and adolescence5.
In particular, prefrontal cortical areas show considerable developmental change across late childhood and adolescence with extensive synaptic pruning and elimination of excitatory synapses shaping the late-maturing cortex5,18.
There is also evidence that environmental risk factors operating across the period of childhood and adolescence can increase risk for both schizophrenia and bipolar disorder, for example, severe childhood abuse has been associated with an increased risk of both disorders19–21, and maternal loss prior to the age of 5 has been associated with bipolar disorder22, while cannabis use has been reported to have greater effects on risk for the development of psychosis if exposure occurs prior to or during the adolescent period5,23,24.
One difficulty in interpreting the salience of these findings is that the causal nature of these candidate risk factors has yet to be firmly established.
Genetic risk for both conditions is highly polygenic, the risk architectures including a large number of common variants, which collectively account for a significant proportion of heritability for these conditions30,31.
As the rare mutations that contribute to schizophrenia also contribute to neurodevelopmental disorders including intellectual disability, autism, ADHD and developmental delay, these findings have contributed to the development of a “neurodevelopmental continuum” model in which schizophrenia is considered to be associated with a greater load of early neurodevelopmental insults than bipolar disorder16,34,35.
Previous studies examining the expression of the top genome-wide association study (GWAS) common variant risk-associated loci for schizophrenia in post-mortem tissue have supported a high level of expression in prenatal brain, consistent with the view that risk for schizophrenia may have early neurodevelopmental origins4,36–39.
However, less is known about the early expression of bipolar-associated genes, or the comparative profile of risk gene expression for schizophrenia and bipolar disorder across development and into adulthood.
Here, we have used data from large-scale GWAS of schizophrenia and bipolar disorder combined with gene expression data across development from the BrainSpan data set40,41, to examine the dynamic expression of genes harbouring common risk variants across developmental stages from prenatal life to adulthood.
Goethe University Frankfurt
Sebastian Lobentanzer – Goethe University Frankfurt
The image is credited to Sebastian Lobentanzer.
Original Research: Open access
“Integrative Transcriptomics Reveals Sexually Dimorphic Control of the Cholinergic/Neurokine Interface in Schizophrenia and Bipolar Disorder”. Sebastian Lobentanzer et al.
Cell Reports doi:10.1016/j.celrep.2019.09.017.