Scientists have identified a genetic mechanism linking brain chemicals to schizophrenia

Scientists have found how the brain chemical dopamine is linked to schizophrenia.

Researchers inspecting postmortem brains verify a long-held speculation that explains the hyperlink between neurotransmitters and the debilitating illness.

What does the brain chemical dopamine have to do with schizophrenia? It’s a query that has vexed scientists for over 70 years, and now researchers on the Lieber Institute for Brain Development (LIBD) consider they’ve solved the puzzle. This new understanding could lead on to higher remedies for schizophrenia, an usually devastating brain illness characterised by delusions, hallucinations and different types of psychosis.

By finding out the expression of genes within the caudate nucleus of the brain, which is related to emotional decision-making, the researchers proved that neurons don’t precisely management dopamine ranges. They additionally identified a genetic mechanism that controls the movement of dopamine. Their outcomes have been revealed within the journal at the moment (November 1). Nature Neuroscience.

According to the World Health Organization (WHO), roughly 1 in 300 folks worldwide endure from schizophrenia, affecting roughly 24 million folks. This determine will increase to 1 in 222 adults.

“Until now, scientists have not been ready to decipher whether or not the dopamine connection was a causative issue or the one means to deal with schizophrenia,” stated Daniel R. Weinberger, one of many authors of the examine. “We have the primary proof that dopamine causes schizophrenia.” Weinberger is the chief govt officer and director of the Lieber Institute.

Dopamine, a kind of neurotransmitter, acts as a chemical messenger that sends alerts to neurons – the brain’s nerve cells – to change exercise and conduct. Dopamine is the reward neurotransmitter that enables folks to expertise pleasure.

According to the National Institute of Mental Health, schizophrenia is without doubt one of the prime 15 main causes of incapacity worldwide. People with this dysfunction endure from psychotic signs comparable to hallucinations, delusions, and thought issues, in addition to decreased feelings, decreased motivation to obtain targets, difficulties with social interactions, impaired motion, and cognitive impairment. Symptoms often start in adolescence or early maturity, however cognitive impairment and strange behaviors can happen in childhood. Current remedies for schizophrenia embrace antipsychotic drugs, which deal with the signs of psychosis however not the trigger.

“One of the primary unwanted side effects of the medication used to deal with schizophrenia is the dearth of delight and pleasure,” says Dr. Jennifer Erwin, an investigator on the institute and co-author of the report. “Theoretically, if we may goal the dopamine receptor with particular medication, this may very well be a new remedy technique that will not restrict the affected person’s happiness.”

Scientists have recognized for many years that irregular ranges of dopamine have some connection to psychosis and are an necessary consider schizophrenia.[{” attribute=””>Alzheimer’s disease, and other neuropsychiatric disorders. Drugs that increase dopamine in the brain, such as amphetamines, are known to cause psychosis. Drugs that treat psychosis do so by reducing dopamine activity.

These observations have inspired generations of scientists to try to understand whether – and how – an imbalance of dopamine actually relates to schizophrenia. Dopamine transmits information in the brain by interacting with proteins on the surface of brain cells, called dopamine receptors. By studying those receptors, scientists at the Lieber Institute have come up with novel evidence confirming that dopamine is a causative factor for schizophrenia. 

The investigators examined hundreds of post-mortem specimen brains donated to the Lieber Institute from over 350 individuals, some with schizophrenia and others without psychiatric illness. They chose to focus on the caudate nucleus, a part of the brain that is critically important for learning how to make complex ideas and behaviors more automatic and intuitive, but also because it has the brain’s richest supply of dopamine. They also studied a region of the human genome that large international genetic studies have identified as being connected with the risk of schizophrenia. This region contains the genes for the protein receptors that respond to dopamine, which points to the dopamine-schizophrenia connection. But while genetic data suggest at most a role of dopamine receptors at risk for schizophrenia, the data are not conclusive and do not identify what the relationship actually is. The investigators at the Lieber Institute went critically further in discovering the mechanisms that make dopamine receptors a risk factor.

The mechanism exists specifically in a subtype of the dopamine receptor, called the autoreceptor, which lies on the “male” side of the connection between neurons, the presynaptic terminal. This autoreceptor regulates how much dopamine is released from the presynaptic neuron. If autoreceptors are compromised, the flow of dopamine within the brain is poorly controlled, and too much dopamine flows for too long.

The investigators found that decreased expression of this autoreceptor in the brain explains the genetic evidence of risk for illness. This is consistent with the prevailing hypothesis that too much dopamine plays a role in psychosis, and strong evidence that the dopamine-schizophrenia riddle has at last been solved.  

The pioneering neuroscientist Dr. Sol Snyder hailed the study as a breakthrough many decades in the making. Dr. Snyder is a distinguished service professor of neuroscience, pharmacology, and psychiatry and founder of the Department of Neuroscience at the Johns Hopkins University School of Medicine, which bears his name. He was the scientist who discovered that antipsychotic drugs work by reducing brain dopamine.

“There’s lots of muddled data indicating the relevance of dopamine and dopamine receptors in schizophrenia,” said Dr. Snyder, who was not involved in this research project. “The key thing these researchers have done is to collect data that puts it all together and in a fashion that is persuasive in establishing that dopamine systems are out of kilter in schizophrenia, and that is causal to the disease.” 

“For decades, people have debated the dopamine connection to schizophrenia,” Dr. Snyder said. “They used to say, ‘Well, this is interesting to speculate about, but there’s no solid evidence.’ But now that we have much more rigorous data available, we keep coming back to the same story. You don’t have to call it a hypothesis anymore.” 

Reference: “Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes” 1 November 2022, Nature Neuroscience.
DOI: 10.1038/s41593-022-01182-7

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