Schizophrenia: Scientists may have finally solved a 70-year riddle

Scientists from the Lieber Institute for Brain Development claim that they've solved a 70-year-old-riddle about schizophrenia.

Challenged the scientists over decades, they revealed the brain chemical dopamine relates to schizophrenia, the often-devastating brain disorder characterized by delusional thinking, hallucinations, and other forms of psychosis.  

The study's findings were published in the journal Nature Neuroscience today.

The researchers discovered physical proof that neuronal cells cannot precisely control dopamine levels through their investigation of the expression of genes in the caudate nucleus, a part of the brain associated with emotional decision-making. They also discovered the genetic mechanism that regulates the flow of dopamine.

“Until now, scientists have been unable to decipher whether the dopamine link was a causative factor or solely a way to treat schizophrenia. We have the first evidence that dopamine is a causative factor in schizophrenia,” said Daniel R. Weinberger, M.D., chief executive and director of the Lieber Institute and a co-author of the study.

The importance of dopamine

Dopamine affects many bodily functions, including memory, movement, motivation, mood, and attention span. Generally, actions and activities that expect rewards increase dopamine levels in the brain. Many addictive drugs work by increasing dopamine levels.

As said in the release, dopamine is a neurotransmitter that operates as a chemical messenger, sending signals between neurons (nerve cells in the brain) to affect their activity and behavior. Dopamine is also the reward neurotransmitter that allows us to experience a pleasure.

“One of the major side effects of the drugs used to treat schizophrenia is lack of pleasure and joy,” said Dr. Jennifer Erwin, an investigator at the Institute and one of the report's authors.

“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.” 

Scientists have long recognized that abnormal dopamine levels are crucial in schizophrenia, Alzheimer's disease, and other neuropsychiatric illnesses. These findings have prompted generations of scientists to investigate if - and how - a dopamine imbalance is related to schizophrenia.

Examined hundreds of post-mortem brains

The researchers examined hundreds of post-mortem specimen brains contributed to the Lieber Institute by more than 350 people, some of whom had schizophrenia and others who did not have a psychiatric disorder.

They opted to concentrate on the caudate nucleus, a portion of the brain vital for learning to make complicated concepts and behaviors more automatic and intuitive and having the brain's richest source of dopamine.

Additionally, they looked at a region of the human genome linked to the risk of schizophrenia in numerous large-scale international genetic investigations. The presence of dopamine-responsive protein receptor genes in this region suggests a link between dopamine and schizophrenia.

The results are inconclusive and do not specify the association, even though genetic data at most show a function for dopamine receptors in schizophrenia risk.

The researchers at the Lieber Institute made significant advancements in understanding the mechanics underlying the risk factor for dopamine receptors.

Abstract:

Most studies of gene expression in the brains of individuals with schizophrenia have focused on cortical regions, but subcortical nuclei such as the striatum are prominently implicated in the disease, and current antipsychotic drugs target the striatum’s dense dopaminergic innervation. Here, we performed a comprehensive analysis of the genetic and transcriptional landscape of schizophrenia in the postmortem caudate nucleus of the striatum of 443 individuals (245 neurotypical individuals, 154 individuals with schizophrenia and 44 individuals with bipolar disorder), 210 from African and 233 from European ancestries. Integrating expression quantitative trait loci analysis, Mendelian randomization with the latest schizophrenia genome-wide association study, transcriptome-wide association study and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets.