Schizophrenia's origins in the brain may have been found - study

Schizophrenia has been linked to the protein SAP97 when it can't function. But nobody has known what this protein even does or where it does it – until now.

 The brain (illustrative). (photo credit: PIXABAY)
The brain (illustrative).
(photo credit: PIXABAY)

Schizophrenia is one of the most infamous mental illnesses around, affecting around 20 million people worldwide, according to the World Health Organization (WHO,) and with a wide range of symptoms such as hallucinations, memory loss, paranoia and more. But exactly how it forms has never been exactly understood by experts.

But a new study may have changed that, pinpointing where in the brain it likely originates.

Published in the peer-reviewed academic journal Nature Communications, the study identified these locations by focusing on a specific protein that was associated with schizophrenia. Based on its location, it shows where in the brain the mental illness comes from, which can pave the way to a greater understanding of the psychiatric disorder and could lead to improved treatment in the future.

What is schizophrenia? What are its symptoms?

Schizophrenia is a mental illness, a psychiatric disorder that can cause a wide range of different symptoms. 

Mental health [illustrative] (credit: PIXABAY)Mental health [illustrative] (credit: PIXABAY)

It is chiefly characterized by psychotic episodes when someone loses touch with reality in a variety of ways. The condition also can cause altered perceptions such as hallucinations, hearing voices that aren't there and other sensory distortions. It can also cause delusions, which can mean severe and irrational paranoia or other beliefs unsupported by any facts and can also cause disorganized speaking and thinking.

The effects on the brain can also lead to memory and information processing issues, trouble making decisions and paying attention. It can also manifest in severe social withdrawal and functionality, less ability to feel pleasure and a flat effect, which is defined as not using facial expressions or tone of voice to convey expressions.

How do you get schizophrenia?

There are a number of things experts have deduced about this, which have been documented by the National Institute for Mental Health (NIMH).

For one thing, though it is possible for symptoms to manifest at a young age, typically schizophrenia only begins to show in adolescence.

Theories exist that environmental influence can play a role, like stressful surroundings, viruses, nutritional problems before birth and living in poverty.

What we do know is that the condition seems to be, to an extent, hereditary and genetic. However, being in the same family as someone who has schizophrenia does not mean you for sure will. Exactly how this genetic process works is not fully understood, and it is not yet possible to test it with genetic information.

So where does it come from in the brain?

That's where the new study comes in.

Researchers from the University of Southern California (USC) Dornsife College of Letters, Arts and Sciences focused on a specific protein known as synapse-associated protein 97, also known as SAP97.

This protein itself is rather mysterious, and scientists know it exists but don't really understand what it does or where it does it. In fact, prior studies on SAP97 have brought back conflicting data.

What was determined over the course of many different studies over the years was that SAP97 plays some kind of role in schizophrenia. More specifically, an association between schizophrenia and when SAP97 isn't able to properly function and do whatever it is supposed to do.

This exact link has been highlighted in different ways. One study noted a gene encoded in SAP97, DLG1, was identified as a possible hub of schizophrenia-related activity. Mutations in SAP97 were also spotted in schizophrenia patients, and mutations resulting in losing a DLG1 allele were noted to cause one to be 40 times more likely to develop schizophrenia. 

Why does this happen?

Scientists could never quite determine that. While it seemed certain that SAP97 and its gene DLG1 played a role in schizophrenia when they were not able to function properly, the fact that no one understood what SAP97 does in the first place has made it frustratingly difficult to actually understand this process at all.

Making this even more confusing is that SAP97 is at the very least known to be what is known as a Membrane-Associated Guanylate Kinase (MAGUK) protein. This would mean that it should be regulating glutamatergic signaling between neurons in the brain and influence the creation and storage of memories. However, it has never been shown doing this at all.

The study

So if SAP97 isn't present where it should be, where is it?

To find this out, the researchers in the new study decided to look elsewhere.

SAP97 was not in any of the parts of the brain it would traditionally be present in. So with that in mind, the researchers looked at a place that was instead linked, in theory, to schizophrenia. 

That location is the dentate gyrus, a part of the hippocampus that controls contextual episodic memory, which is the conscious recollection of life experiences. Essentially, this is where you would remember what happened when it happened and where it happened.

And as mentioned earlier, this type of memory is often distorted and altered in schizophrenia, which could mean that the dentate gyrus, which controls this type of memory, would be altered in someone with schizophrenia. 

And if SAP97 is linked to this, then maybe, the mysterious protein could be found there as well.

So the scientists got to work. They examined the brains of rats with damaged SAP97 and looked at the dentate gyrus for changes.

And they found them.

When SAP97 function is reduced, the neurons in the dentate gyrus had extreme spikes in glutamatergic signaling. This type of spike produces severe alterations in contextual episodic memory, a classic symptom of schizophrenia.

Since SAP97 was inhibited, the implication is that the mysterious protein's job is to regulate glutamatergic signaling in the dentate gyrus.

This is a major breakthrough in identifying the role and location of this protein in the brain and indicating where schizophrenia symptoms may emerge.

And the researchers hope to build on this, launching further studies to look for other areas of the brain where SAP97 may be active, and try to find if other mutations linked to schizophrenia may cause similar glutamatergic signaling increases as it does in the dentate gyrus.

Consequently, knowing more about this condition can lead to better treatment options.

Currently, the most common treatment for schizophrenia is antipsychotic medication alongside therapy and social support. However, these medications can have a host of side effects that can be very disruptive to daily life, which has led people to stop taking them. However, that can be extremely dangerous and may make symptoms worsen. Further, medications don't always work for everyone, or fully treat all symptoms. Some even need to use other drugs like clozapine, though that can have serious side effects and regular blood testing is needed, which can be difficult – though a recent innovation by Israel's Ben-Gurion University of the Negev hopes to change that.

More effective treatment can make life better for millions of people with schizophrenia around the world.