Is dopamine dysregulation responsible for schizophrenia?

Is dopamine dysregulation responsible for schizophrenia?

Post-mortem genetic analysis of the brains of patients with schizophrenia suggests that dysfunction of dopamine receptors in the caudate nucleus may be the cause of the disorder.

Researchers have identified a mechanism on the dopamine receptor, known as the autoreceptor, that regulates the amount of dopamine released by the presynaptic neuron. Impairment of this autoreceptor leads to poorly controlled dopamine release and excessive dopamine flow.

The researchers found that decreased expression of this autoreceptor explains the genetic evidence for schizophrenia risk and, using a suite of statistical routines, they showed that this relationship is likely causal.

“Our research supports the scientific hypothesis that too much dopamine plays a likely causative role in psychosis and precisely how this is based on genetic factors,” said study researcher Daniel Weinberger, MD, director and CEO of the Lieber Institute for Brain Development. Medscape Medical News.

“Drugs that treat the symptoms of psychosis by simply blocking dopamine receptors have serious side effects… Theoretically, scientists could now develop therapies that target these faulty autoreceptors to treat this devastating disease with fewer effects. secondary,” he said.

The study was published online November 1 in Natural neuroscience.

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“Large international genetic studies known as genome-wide association studies (GWAS) have identified hundreds of regions of the human genome harboring potential risk genes for schizophrenia,” Weinberger said.

“However, these regions are still poorly resolved in terms of specific genes, and treatments and diagnostic techniques are far from where they should be.” Additionally, “treatments for schizophrenia address the symptoms of psychosis but not the cause,” he said.

“For more than 70 years, neuroscientists have suspected that dopamine plays a key role in schizophrenia, but what kind of role, exactly, has remained a mystery,” Weinberger noted. “It has held pride of place in the main schizophrenia hypothesis for over 60 years – the so-called ‘dopamine hypothesis’.”

Dopamine-reducing antipsychotic drugs “are the primary medical treatments, but they cause serious side effects, including an inability to experience pleasure and joy – a sad reality for patients and their families,” he said. for follow-up.

The current study “sought to understand how dopamine acts in schizophrenia” using “genetic and transcriptional landscape analysis” of the post-mortem caudate nucleus of 443 donors (245 neurotypical, 154 with schizophrenia, and 44 with bipolar disorder).

Brain samples were from individuals of diverse ancestry (210 were of African descent [AA] and 2,233 were of European ancestry [EA]).

New treatment target?

The researchers performed an analysis of quantitative transancestral expression trait loci (eQTLs), genetic variants that explain variations in the expression levels of genes, which are expressed in the caudate, annotating “hundreds of specific traits to the caudate”. cis-eQTL.”

Then they integrated this analysis with gene expression that emerged from the latest genome-wide association study (GWAS) and transcriptome-wide association study, identifying hundreds of genes that “showed a potential causal association with schizophrenia risk in the caudate nucleus,” including a specific isoform of the dopamine D2 receptor, which is upregulated in the caudate nucleus of people with schizophrenia.

“If the autoreceptors aren’t working properly, the flow of dopamine in the brain is poorly controlled and too much dopamine is flowing for too long,” Weinberger said.

In particular, they observed “expanded differential gene expression” for schizophrenia in 2701 genes in people with schizophrenia (compared to those without): glial cell-derived neutrophic factor antisense RNA (GDNF-AS1) was a “top-up” gene and tyrosine hydroxylase (E), which is a rate-limiting enzyme of dopamine synthesis, was a “down-regulated” gene. Dopamine receptors DRD2 and DRD3 were differentially expressed.

With that done, they looked at the effects of antipsychotic drugs that target D2 regions on gene expression in the caudate by testing the differences between people with schizophrenia who were taking antipsychotics at the time of death, those who were not taking antipsychotics at the time of death. antipsychotics at the time of death (n = 104 and 49, respectively) and neurotypical individuals (n = 239).

There were 2692 differentially expressed genes (DEG) between individuals taking antipsychotics compared to neurotypical individuals (false discovery rate [FDR] < .05). In contrast, there were only 665 DEG (FDR < 0.05) between those not taking antipsychotics and neurotypical individuals.

“We found that antipsychotic drugs have a dramatic influence on caudate gene expression,” the researchers note.

They then developed a novel approach to “infer gene networks from expression data”. This method is based on deep neural networks, obtaining a “low-dimensional representation of the expression of each gene across individuals”. The representation is then used to construct a “gene neighborhood graph and assign genes to modules”.

This method identified “several enriched modules for genes associated with schizophrenia risk”. Expression representations captured in this approach placed genes in “biologically meaningful neighborhoods, which may provide insight into potential interactions if these genes are targeted for therapeutic intervention,” the authors summarize.

“Now that our new research has identified the specific mechanism by which dopamine plays a causal role in schizophrenia, we hope to have opened the door to more targeted drugs or diagnostic tests that could improve the lives of patients and their families. “, Weinberger said.

No causal link?

Commenting for Medscape Medical News, Rifaat El-Mallakh, MD, director of the Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Kentucky, called it “an excellent study performed by an excellent research group” which “fills an important gap in our research database.”

However, El-Mallakh, who was not involved in the research, disagreed that the results show causation. “The data that can be gleaned from this study is limited and the design has significant limitations. As with all genetic studies, this is an association study. It tells us nothing about the relationship of cause and effect between genes and disease.”

“We don’t know why genes are associated with disease. Genetic overrepresentation can have many causes, and more so when the data is a convenience sample. As the authors noted, much of what they observed was probably related to the effect of the drugs. I don’t think this study specifically tells us anything clinically,” he added.

The study was supported by LIBD, the BrainSeq Consortium, an NIH grant to two of the authors, and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation to one of the authors. Weinberger did not report any relevant financial relationships. Disclosures for other authors are listed with the article. El-Mallakh said no specific financial relationships relevant to the study, but said he is a speaker for several companies that manufacture antipsychotics.

Nat Neurosci. Published online November 1, 2022. Summary 1, Summary 2

Batya Swift Yasgur MA, LSW, is a freelance writer with a consulting firm in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoirs of two brave Afghan sisters who told her their story).

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