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Developmental Biology - Brain|
Reversing Symptoms of Schizophrenia
These findings, published in Neuron, challenge the generally accepted belief that cellular disruptions underling memory issues in schizophrenia cannot be repaired once symptoms arise. They also hold immense promise for treating the more than 21 million people worldwide already diagnosed with schizophrenia.
"Schizophrenia is thought a neurodevelopmental disorder that begins years before it can actually be diagnosed, making the disease's underlying aspects extremely difficult to understand and treat. 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."
Schizophrenia's most well-known symptoms - paranoia, auditory hallucinations and delusions - can often be controlled with antipsychotic medication. But disruptions to working memory, an underlying problem that affects virtually all patients, have remained largely untreatable. This has spurred renewed efforts to target the disease's underlying causes. Such memory problems can make it difficult to maintain relationships or a job, essentially cutting off people with schizophrenia from the world around them.
For this study, the research team focused on gene SETD1A, which makes a protein that can regulate, or change, the activity of other genes. Scientists have long known that this gene is important for embryos to grow properly.
Brain cells called neurons in the animals' prefrontal cortex, a brain region critical for memory and complex behaviors, looked markedly different in these mice. Normally, neurons in this region have extendable branches. They use these branches to link up with other neurons and communicate with their cellular neighbors. But the neuronal branches of the SETD1A-deficient mice were short and stunted. SEE IMAGE:SETD1A-deficient mice (left center)
"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.
Searching for ways to fix the cells, the team began to think about ways to manipulate SETD1A. Dr. Gogos and his lab teamed up with Zuckerman Institute Principal Investigator and geneticist Stavros Lomvardas, PhD, and members of the Lomvardas lab, to tease apart SETD1A's role in the brain.
"We found SETD1A to be a genomic multitasker. 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."
Further complicating this work was the fact that there are no known means for manipulating SETD1A pharmacologically, such as with a drug, so the team identified a workaround. They found another gene called LSD1 (unrelated to the psychoactive substance LSD). When switched off, this gene nullifies SETD1A's harmful effects.
"Within a few weeks of administering an LSD1 inhibitor, the animals' memory improved dramatically," said Dr. 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 not only acting on the memory deficits linked to schizophrenia but on the underlying molecular mechanisms that drive them.
"These results also illustrate a new role of SETD1A in the brain," says Dr. 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 axon growth."
In fact, SETD1A likely impacts additional aspects of brain function. The team hypothesizes that SETD1A influences a host of other factors - such as other genes and proteins - and that the combined activity of all these factors ultimately cause the memory deficits observed in mutant mice.
Psychiatric disorders like schizophrenia have proven difficult to treat, in part because they lack a single cause, a single broken gene. With multiple genetic and environmental factors likely at play, these findings could pave the way to personalized medicines designed for individuals with SETD1A mutations - and perhaps even broader treatment strategies.
"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," explains Dr. Gogos, also 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."
Moving forward, the team hopes to further illustrate the roles of SETD1A. They hope to expand and fine-tune 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. We are exploring whether they could be repurposed to treat schizophrenia patients."
• Cognitive and circuitry deficits in a mouse model of SETD1A, a schizophrenia risk gene
• Reinstating Setd1a or antagonizing LSD1 activity in adulthood rescues deficits
• Setd1a binds promoters and enhancers with a striking overlap with Mef2 on enhancers
• Evolutionarily conserved Setd1a-bound enhancers may regulate psychiatric risk genes
SETD1A, a lysine-methyltransferase, is a key schizophrenia susceptibility gene. Mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics accompanied by working memory deficits. We show that Setd1a binds both promoters and enhancers with a striking overlap between Setd1a and Mef2 on enhancers. Setd1a targets are highly expressed in pyramidal neurons and display a complex pattern of transcriptional up- and downregulations shaped by presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice. Our findings advance understanding of how SETD1A mutations predispose to schizophrenia (SCZ) and point to novel therapeutic interventions.
Jun Mukai, Enrico Cannavò, Stavros Lomvardas, Joseph A. Gogos Gregg Crabtree, PhD, Ziyi Sun PhD, Anastasia Diamantopoulou, PhD, Pratibha Thakur, Chia-Yuan Chang, Yifei Cai PhD, Atsushi Takata PhD and Bin Xu PhD.
Columbia University's Mortimer B. Zuckerman Mind Brain Behavior Institute brings together a group of world-class scientists and scholars to pursue the most urgent and exciting challenge of our time: understanding the brain and mind. A deeper understanding of the brain promises to transform human health and society. From effective treatments for disorders like Alzheimer's, Parkinson's, depression and autism to advances in fields as fundamental as computer science, economics, law, the arts and social policy, the potential for humanity is staggering. To learn more, visit: zuckermaninstitute.columbia.edu.
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Images of axon branching of WT (normal) mice (left) compared to SETD1A-deficient mice (left center). SETD1A-deficient mice injected with an LSD1 inhibitor (right center) rescued axonal growth to near-normal levels and counteracted the behavioral deficits. LSD1 inhibitor had no effect on WT mice (right). CREDIT Jun Mukai/Gogos lab/Columbia's Zuckerman Institute.