Autoreceptor absence fuels dopamine dysregulation in schizophrenia

Generations of studying the root cause of schizophrenia have largely converged around a single theory: the “dopamine hypothesis,” which postulates that a combination of genetic susceptibility, substance abuse and environmental stress lead to too much dopamine signaling in the brain. Yet it has remained unclear exactly how excess dopamine leads to psychosis and other schizophrenia symptoms.

Now, scientists from Maryland’s Lieber Institute for Brain Development believed they’ve solved the puzzle. In the results of a study published Nov. 1 in Nature Neuroscience, the researchers reported that they’ve identified the mechanism behind dopamine dysregulation in schizophrenia. The results of their work could be applied to developing better treatments for the condition and might even explain why some drugs in clinical trials could be an improvement over existing antipsychotics.

“The research has been hovering around dopamine’s involvement in psychosis, but it’s never been clear that it’s anything beyond a way to treat,” Daniel Weinberger, M.D., study co-author and chief executive of the Lieber Institute, told Fierce. “Now it’s clear that it’s a causative factor.”

The researchers’ findings were made possible by a unique source of data: the post mortem brains of more than 350 individuals with and without schizophrenia, which had been donated to the Lieber Institute. The donor brains gave the researchers a way to analyze how gene expression translated to tissue changes in previously understudied regions of the brain, like the caudate nucleus. While this dopamine-rich region had previously been theoretically linked with schizophrenia and is thought to be the target of many schizophrenia drugs, it hadn’t yet been examined in depth.

“All of the prior studies except for two were in the prefrontal cortex,” Weinberger explained. With such a robust source of data available, “it was time to take the caudate seriously,” he said.

To figure out where to look first, Weinberger’s team conducted a genome- and transcriptomewide analysis of all the genes expressed in the caudate to see whether any were found that had been associated with an increased risk for schizophrenia in genomewide association studies. They identified several matches that were involved in dopamine regulation, including one that was linked to expression of the dopamine autoreceptor on presynaptic neurons, or cells that send signals. One might think of autoreceptors as sensors that monitor the levels of a neurotransmitter or hormone released by a cell; if the sensor detects that enough of a substance has been released, it will keep the cell from releasing more.

This was the first time anyone had looked at autoreceptors on presynaptic neurons in schizophrenia, Weinberger said. Until recently, most research—and most drugs—have focused on postsynaptic neurons, or the neurons that receive signals from presynaptic cells.

“The story of dopamine has always been that there’s too much, so the assumption was that there’s an increase at the postsynaptic receptor,” he explained. “If there’s too much dopamine, that must be because there’s too many receptors.”

Instead, the problem appears to be upstream: Some people are genetically inclined to develop fewer autoreceptors on presynaptic neurons in the caudate. This means the cells can’t sense when too much dopamine has been released, so it keeps flowing unchecked—leading to psychosis.

Weinberger likened it to a spigot that can’t be turned off.

“The shock here was that there’s decreased autoreceptors, so the spigot didn’t shut down the way it was supposed to,” he said. “If the presynaptic autoreceptor is diminished, it doesn’t respond as adequately.”

Many of the antipsychotics in use block dopamine receptors in postsynaptic neurons. While this stops hallucinations and delusions, it results in what have been described as “Parkinsoninan” side effects—uncontrollable movements and restlessness.

The mechanism also doesn't help or can even worsen the "negative" symptoms of schizophrenia, such as apathy, and leave individuals unmotivated and unable to enjoy life. While the newer atypical antipsychotics act on multiple neurotransmitters and thus have better side-effect profiles, there's still much room for improvement. 

In contrast, drugs that regulate dopamine release at the level of presynaptic autoreceptors could theoretically improve psychotic symptoms without the side effects caused by blocking dopamine binding. A class of drugs that act regulate dopamine levels through presynaptic muscarinic receptors could have a similar effect, Weinberger noted.

Two examples are Cerevel’s emraclidine and Karuna Therapeutics KarXT, both of which are in clinical trials. In August, Karuna posted encouraging phase 3 results that showed KarXT improved patient’s hallucinations and delusions as well as their ability to enjoy life.