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Surprise Results in experiments with mice reverse core symptom of schizophrenia

A drug that is currently being developed to treat leukemia has delivered a surprise in mouse studies by reversing a previously untreatable symptom of schizophrenia – impairment of spatial working memory.

In humans, schizophrenia has proved extremely difficult to understand, even less treat. The neuropsychiatric disorder has a number of symptoms that affect the person's mood, behavior and functional ability. Cognitive impairment, which may include memory problems, is considered a core function of schizophrenia.

Yet, there are no standardized treatments for treating schizophrenia, either therapeutically or pharmaceutically. The drugs we currently have for schizophrenia can greatly control psychotic symptoms, not cognitive.

Researchers at Columbia University now believe that there may be a way to treat schizophrenia-associated working memory deficits after all.

Using a mouse model, the team successfully reversed a mutation in the gene SETD1

A, which they had previously associated with the disorder; mutations to this specific gene "provide a major increase in the risk of disease," the team writes in its paper.

"We were surprised that restoration of SETD1A activity in the brain of adult mice restores their learning," neuroscientist Joseph Gogos of the Columbia Zuckerman Institute told ScienceAlert, "which means that the damage done by the mutation during brain development is not irreversible . "

The results are a promising step forward, says Gogos, as "a way to use knowledge from genetic studies to identify drugs that restore normal cognitive and cellular function in the adult brain after the onset of the disease."

While Mice not getting schizophrenia showed the animals with this genetic mutation sign of lack of space, as they could not navigate in a simple maze. Not only that, but their prefrontal cortex looked significantly different from the mice without the mutation, which revealed much shorter neurons that look like their branches had been stunted.

Fixing these cells would require a drug of some kind that could manipulate the SETD1A gene. The problem was that there was no such drug, so Gogos and his colleagues had to be smart.

In their digging, they found that when another gene, called LSD1, was turned off, the harmful effects of SETD1A disappeared. Repositioning of the drug LSD1 inhibitor seemed like a logical shot.

"Within a few weeks of administering an LSD1 inhibitor, animal memory improved dramatically," says neuroscientist Jun Mukai.

"Even more striking was what we observed in animal brains: their axons grew in similar patterns as we see in a healthy mouse brain."

Even better, the authors say that this drug acted on the underlying mechanisms that drives the memory deficits, rather than

"We have found definitive evidence that not only [SETD1A] is indicative of early development, but it also supports ongoing functions of the adult brain, such as axonal growth," claims neuroscientist Enrico Cannavó. [19659003] The team now hopes to use human genetic studies to understand disease mechanisms in model organisms such as mice, so that they can identify pathways for future drugs.

"These are animal models of mutations that we know (unequivocally) increase the risk of schizophrenia in humans," Gogos told ScienceAlert.

"By analyzing how these mutations affect the mouse brains, we can conclude how they can affect the development and function of the human brain."

The research was published in Neuron .

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