An international research team headed by scientists at Columbia University restored normal working memory in a mouse model of schizophrenia (SCZ). The achievement, demonstrated using both genetic, and pharmacological approaches, effectively reversed in adult mice a core symptom of the neuropsychiatric disorder that has proven almost impossible to treat in humans. The work also challenges the common assumption that cellular changes that underlie memory issues in schizophrenia cannot be repaired once symptoms have developed.
“Schizophrenia is thought to be a neurodevelopmental disorder that begins years before it can actually be diagnosed, making the disease’s underlying aspects extremely difficult to understand and treat,” said research lead Joseph Gogos, MD, PhD, a principal investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute. “Today’s paper shows a promising way forward: 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 disease.”
Cogos and colleagues at Columbia University, together with collaborators in Japan and China, report their findings in Neuron, in a paper titled, “Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice.”
Schizophrenia affects more than 21 million people worldwide. The most well-known symptoms of the disorder, which include paranoia, auditory hallucinations, and delusions, can now often be controlled using antipsychotic drugs. In contrast, disruption to working memory, an underlying problem that affects nearly all schizophrenia patients, can’t be treated. Working memory is a key brain process that allows us to retain and recall information as we navigate our everyday tasks. An example is being able to remember a new phone number long enough to dial it. For people with schizophrenia, impaired working memory can alter reasoning, perception, and decision making, and make it difficult to maintain relationships or a job.
Prior research has linked complex neuropsychiatric disorders such as schizophrenia with what may be individually rare, but collectively common spontaneous and inherited mutations, the investigators wrote. One of the key known schizophrenia risk genes is the lysine-methyltransferase gene SETD1A. Scientists had long known that the gene was important for embryos to grow properly, but it was in 2014 that Gogos and his collaborators found that mutations in SETD1A are also associated with schizophrenia in people. “SETD1A is a confirmed SCZ risk gene, and SETD1A mutations confer a large increase in disease risk,” the authors wrote.
For their reported studies the researchers examined the behavior of mice that had been engineered to carry only one normal copy of the SETD1A gene, and so only produce about half the normal amount of the gene’s protein. They found that compared with normal mice, these Setd1a+/- animals demonstrated deficits to their working memory such that they had difficult navigating a simple maze, although the SETD1A-deficient rodents were just as capable of performing other cognitive tasks as were the wild-type control mice.
Further studies showed that neurons in the prefrontal cortex (PFC) of the engineered mice looked very different to those in the normal mice. Neurons in the PFC region of the brain typically have extendable branches, which link up and communicate with other neurons. In contrast, the neuronal branches of the SETD1A-deficient mice were short and stunted. “The neurons’ misshapen axons prevented them from making the necessary connections to neurons next to them or in other parts of the brain,” said Jun Mukai, PhD, the paper’s co-first author, who was an associate research scientist in the Gogos lab.
Having demonstrated working memory deficits and neuronal changes in the schizophrenia model mice, the Gogos team set out to find ways to potentially fix the cells. One possible option might involve manipulating SETD1A itself. With this in mind the Gogos lab teamed up with Stavros Lomvardas, PhD, Zuckerman Institute principal investigator and geneticist, to try to uncover more about SETD1A’s role in the brain. “We found SETD1A to be a genomic multitasker,” said Enrico Cannavó, PhD, a postdoctoral research scientist in the Lomvardas lab and another of the paper’s co-first author. “Sometimes SETD1A turns a gene on, while other times it turns a gene off. This ability to dial up and down gene activity makes SETD1A complicated to study.”
To see what would happen if they could reinstate SETD1A production, the researchers first used genetic techniques to switch a defective copy of the gene back on in their experimental mice. “The lack of gross structural or neurodegenerative abnormalities in Setd1a-deficient brains prompted us to investigate the possibility of reversing cognitive deficits in adulthood,” they wrote. “We took advantage of the conditional nature of the targeted allele and adopted a genetic method that allows for inducible reactivation of Setd1a in Setd1a+/- adult mice.”
Encouragingly, genetically reinstating SETD1A production in adult schizophrenia model mice improved the working memory deficits. “… our findings indicate that adult Setd1a function reinstatement has substantial effects on ameliorating cognitive deficits, highlighting a broad window of therapeutic opportunity,” the scientists noted.
Ideally, there would be a potential drug treatment for use in human patients with SETD1A mutations, but as there are currently no known pharmacological approaches to manipulating SETD1A, the team had to find an alternative strategy. They identified a histone demethylase gene known as LSD1, which, when switched off, effectively nullified SETD1A’s harmful effects. There are already known drug compounds that can block LSD1, including candidates that are in development for treating leukemia.
Encouragingly, using a drug compound to block LSD1 in the Setd1a+/- schizophrenia mouse model also led to improvements in the animals’ working memory tests. “Within a few weeks of administering an LSD1 inhibitor, the animals’ memory improved dramatically,” said Mukai. “Even more striking was what we observed in the animals’ brains: their axons grew in similar patterns to what we see in a healthy mouse brain.” This observation demonstrated that the LSD1 inhibitor was acting at the level of the underlying molecular mechanisms that drive the memory deficits. “These results also elucidate a new role of SETD1A in the brain,” said Cannavó. “We’ve found definitive proof that not only does it guide early development, but it also supports ongoing functions in the adult brain, such as axonal growth.”
Schizophrenia likely results from the interplay of multiple genetic and environmental elements, so it’s likely that SETD1A impacts on multiple factors that combine to cause the memory deficits observed in mutant mice. The new findings could help to unpick these mechanisms and ultimately pave the way to personalized medicines designed for individuals with SETD1A mutations.
“Although SETD1A mutations exist in a small percentage of all schizophrenia patients, many people diagnosed with the disorder have issues similar to those caused by this mutation,” said Gogos, who is also a professor of neuroscience at Columbia’s Vagelos College of Physicians and Surgeons. “Thus, therapies that are specific to SETD1A may indeed have wider implications for schizophrenia as a whole.”
“While it will be important to determine the specific methylation sites underlying the beneficial effects of LSD1 antagonism, our findings indicate that reactivating Setd1a function or counteracting downstream effects of Setd1a deficiency in the adult brain may be sufficient to ameliorate the manifestation of some neurocognitive phenotype,” the authors concluded.
Moving forward, the scientists hope to further unpick the roles of SETD1A. They also aim to continue their investigations of LSD1 inhibitors as a therapeutic strategy. “Several LSD1 inhibitors are in early-stage clinical trials for treating leukemia and other forms of cancer,” said Gogos. “We are exploring whether they could be repurposed to treat schizophrenia patients.”