HomeScienceGeneticsDopamine dysregulation a causative culprit in schizophrenia?

Dopamine dysregulation a causative culprit in schizophrenia?

A genetic postmortem analysis of the brains of patients with schizophrenia suggests dysfunction of dopamine receptors in the caudate nucleus may cause the condition.

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

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

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

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

The study was published online Nov. 1 in Natural Neuroscience.

Privileged place

“Large international genetic studies known as genome-wide association studies (GWAS) have identified hundreds of regions of the human genome that harbor 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 what they should be.” In addition, “treatments for schizophrenia treat the symptoms of psychosis, not the cause,” he said.

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

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Antipsychotics that reduce dopamine “are the main medical treatments, but they cause serious side effects, including the inability to experience pleasure and joy — a sad reality for patients and their families,” he continued.

The current study “aims to understand how dopamine works in schizophrenia” using “analysis of the genetic and transcriptional landscape” 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 various ancestry (210 were of African descent [AA] and 2233 were of European descent [EA]).

New treatment target?

The researchers performed an analysis of transancestry expression quantitative trait loci (eQTL), genetic variants that account for variations in gene expression levels, which are expressed in the caudate, annotating “hundreds of caudate-specific cis-eQTLs.”

They then integrated this analysis with gene expression emerging from the latest genome-wide association study (GWAS) and transcriptome-wide association study, which identified hundreds of genes that “showed a possible causal relationship to the risk of schizophrenia 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 autoreceptors don’t work properly, the flow of dopamine in the brain is poorly controlled and too much dopamine flows for too long,” Weinberger said.

Specifically, they observed “extensive 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 in the synthesis of dopamine, was a “down-regulated” gene. Dopamine receptors DRD2 and DRD3 were differentially expressed.

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

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

“We found that antipsychotic medication has a major influence on caudate gene expression,” the researchers note.

They then developed a new approach to “derive gene networks from expression data”. This method relies on deep neural networks, providing a “low-dimensional representation of the expression of each gene across individuals.” The representation is then used to build a “gene neighborhood graph and map genes to modules”.

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

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

No causal relationship?

Comment 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 conducted by an outstanding research group” that “fills an important gap” . in our research database.”

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However, El-Mallakh, who was not involved in the study, disagreed that the findings demonstrate causality. “The data that can be extracted 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 cause-and-effect relationship between the genes and the disease.”

“We don’t know why genes are associated with the disease. Genetic over-representation may have multiple causes, especially when the data is a convenience sample. As noted by the authors, much of what they observed was likely related to drug effect. I think not that this study tells us anything specific clinically,” he added.

The study was supported by LIBD, the BrainSeq Consortium, an NIH grant for two of the authors, and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation for one of the authors. Weinberger has reported no relevant financial relationships . Explanations for the other authors are given with the article. El-Mallakh has stated that there are no specific financial relationships relevant to the investigation, but has reported speaking for several antipsychotic drug companies.

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

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

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