Genetic Mechanism Of Dopamine In Schizophrenia Identified

Schizophrenia is a devastating brain disorder characterized by delusional thinking, hallucinations, and other forms of psychosis; how the brain chemical dopamine relates to this disorder has been a mystery for more than 70 years, but researchers at the Lieber Institute for Brain Development (LIBD) believe they have found an answer.

Scientists identified the genetic mechanism that regulates dopamine flow through the brain’s caudate nucleus, a region associated with emotional decision-making, and provided physical proof that neuronal cells lack the ability to precisely control dopamine levels. It is the first evidence that dopamine is a causative factor in schizophrenia.

“Until now, scientists have been unable to decipher whether the dopamine link was a causative factor or solely a way to treat schizophrenia,”

said co-author Daniel R. Weinberger, M.D., director of the Lieber Institute.

Schizophrenia Treatment Potential

Dopamine is a neurotransmitter that operates as a chemical messenger, sending signals between neurons to regulate their activity and behaviour. Dopamine is the reward neurotransmitter that allows us to experience pleasure.

Schizophrenia is one of the top 15 leading causes of disability worldwide, with symptoms including psychosis (such as hallucinations, delusions, and disordered thinking), impaired emotional expression, decreased motivation to achieve goals, difficulty forming and maintaining social relationships, motor impairment, and cognitive impairment.

Symptoms often first occur in late adolescence or early adulthood, though cognitive impairment and peculiar behaviours can sometimes be observed in younger ages. Antipsychotic medicines are used to treat schizophrenia, although these only treat the symptoms of the disorder.

Lack of enjoyment and joy is one of the main side effects of medications used to treat schizophrenia.

“In theory, if we could target the dopamine receptor specifically with drugs, that could be a new strategy for treatment that would not limit a patient’s joy as much,”

said co-author Dr. Jennifer Erwin, an investigator at the Institute.

Abnormal Dopamine Levels

Scientists have known for decades that dopamine levels are linked to psychosis and play a role in schizophrenia, Alzheimer’s disease, and other neuropsychiatric illnesses.

  • Amphetamines and other drugs that boost dopamine in the brain are known to cause psychosis
  • Dopamine activity is reduced by drugs that treat psychosis

These insights have prompted generations of scientists to investigate if – and how – a dopamine imbalance is related to schizophrenia. Dopamine interacts with proteins on the surface of brain cells called dopamine receptors to transmit information in the brain.

Scientists at the Lieber Institute discovered new data confirming that dopamine is a causal factor in schizophrenia by analyzing those receptors.

Caudate Nucleus

The researchers studied hundreds of post-mortem specimen brains donated to the Lieber Institute by over 350 people, some of whom had schizophrenia and others who did not.

They opted to concentrate on the caudate nucleus, a portion of the brain that is vital for learning how to make complicated concepts and behaviours more automatic and intuitive, as well as having the brain’s richest source of dopamine.

They also looked at a region of the human genome that has been linked to the risk of schizophrenia in major multinational genetic research. This area contains the genes for the protein receptors that respond to dopamine, indicating a link between dopamine and schizophrenia.

However, while genetic data suggest that dopamine receptors may play a role in schizophrenia risk, the research is inconclusive and does not specify what the association is. The Lieber Institute researchers moved a key step further in uncovering the mechanisms that make dopamine receptors a risk factor.

Dopamine Autoreceptor Expression

The mechanism is unique to the autoreceptor subtype of the dopamine receptor, which is found on the “male” side of the presynaptic terminal, the junction between neurons. The amount of dopamine released from the presynaptic neuron is controlled by this autoreceptor.

Dopamine flow within the brain is poorly regulated if autoreceptors are damaged, and too much dopamine flows for an extended period of time.

The researchers discovered that lowered expression of this autoreceptor in the brain explains the hereditary evidence of sickness risk. This is consistent with the widely held belief that too much dopamine contributes to psychosis, and it provides strong evidence that the dopamine-schizophrenia puzzle has been solved.

A Long-awaited Breakthrough

Dr. Sol Snyder, a pioneering neuroscientist, welcomed the discovery as a long-awaited breakthrough. Dr. Snyder is a distinguished service professor of neurology, pharmacology, and psychiatry at Johns Hopkins University School of Medicine, where he founded the Department of Neuroscience. He was the scientist who discovered that antipsychotic medications act by decreasing dopamine levels in the brain.

“There’s lots of muddled data indicating the relevance of dopamine and dopamine receptors in schizophrenia. 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,”

Dr. Snyder, who wasn’t involved in this study, said.

“For decades, people have debated the dopamine connection to schizophrenia. 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,”

Dr. Snyder said.

Reference:

Analysis of the caudate nucleus transcriptome in individuals with schizophrenia highlights effects of antipsychotics and new risk genes. Nature Neuroscience. 1-Nov-2022 doi: 10.1038/s41593-022-01182-7