Exploring the Link Between Neural Dysfunction and Psychiatric Disorders
Guoping Feng is the James W. (1963) and Patricia T. Poitras Professor of Brain and Cognitive Sciences at MIT, and a member of MIT’s McGovern Institute and Yang Tan Collective.
Unlike most cells, the 86 billion neurons in the human brain are unable to function autonomously. They require continuous, accurate connections with other neurons.
When the communication between pre-synaptic and post-synaptic terminals breaks down, bad things can happen. Alzheimer’s disease, for example, is caused in part by the build-up of plaques that damage neural connections.
Armed with genomic tools and techniques, biomedical researchers have determined that many neurodevelopmental and psychiatric disorders are caused more by interference from inside the neuron than out. Mutations of genes encoding proteins in the post-synaptic terminal appear to be partially responsible for many of the syndromes related to autism spectrum disorder (ASD), schizophrenia, bipolar disorders, and more.
“The postsynaptic terminal collects and transduces neural signals into electrical and biochemical changes,” says Guoping Feng, the James W. (1963) and Patricia T. Poitras Professor of Brain and Cognitive Sciences at MIT, and a member of MIT’s McGovern Institute and Yang Tan Collective. “It has about ten times more proteins and genes that help build a neural response than the pre-synaptic terminal, and far more of them are linked to brain disorders.”
Feng has greatly broadened our understanding of the link between psychiatric disorders and the post-synaptic terminal. Most notably, he identified neurobiological mechanisms linking ASD to mutations in the gene that creates the SHANK3 protein. Feng is now collaborating on developing gene therapies for ASD based on the research. He has begun investigating how protein mutations affect disorders such as schizophrenia.
Feng is also a leader in developing tools for studying neural function. He recently created an ultra-light sensitive optogenetics tool that enables non-intrusive modulation of neural activity. He has recently begun applying the tool to the study of brain waves (see farther below).
Feng has greatly broadened our understanding of the link between phychatric disorders and the post-synaptic terminal.
Autism spectrum disorder is one of the fastest growing health crises in the US, affecting about one in 37 children. The most severe form of ASD, called monogenic or syndromic ASD, is often caused by single-gene mutations. Most people with ASD, however, have a more sporadic and less severe form of the disorder. These polygenic types of ASD are caused by mutations in multiple genes and proteins, as well as environmental factors.
Feng is focusing his research on the simpler monogenic ASD, with the hope that the research will also shine light on polygenic ASD. Using genetically engineered animal models, Feng has determined how a SHANK3 mutation leads to Phelan-McDermid syndrome (PMS), a type of syndromic ASD.
“Large-scale genomics research has shown that both monogenic and polygenic autism could be caused by defects in the post-synaptic terminal,” says Feng. “We know that SHANK3 is very important for the development of synapses and neural communication. As a scaffolding protein at the post-synaptic terminal, SHANK3 sets up a structure that enables many other proteins to come in, do their job, and leave. That makes it a good model to understand why a single-gene mutation can cause the complex behavior changes found in ASD, including intellectual disability, social interaction deficit, and repetitive behavior.”
By studying and comparing human patients and mouse models, Feng’s team found that each of the symptoms of ASD has a different mechanism at the circuit and cellular level. Yet, at the molecular level, they share the same single-gene mutation in SHANK3.
One of the most recognizable symptoms of ASD, obsessive-compulsive disorder, and Tourette's syndrome, is excessive repetition of actions. Repetitive behavior is caused by dysfunctional brain circuits in the basal ganglia.
For any movement or behavior, the basal ganglia provides two pathways: one that promotes an action and one that inhibits it. “If the pathways are not balanced and the promoting pathway is dominating, you will keep repeating the action,” says Feng. “In repetitive behavior in people with OCD and autism, we have an imbalance that causes the action side to be stronger than the inhibiting side.”
Feng has identified the SHANK3 mutation that causes extreme repetitive behavior and has developed a gene therapy, in which the mutation is corrected. “We basically replace the defective SHANK3 gene with a normal copy,” says Feng. “We have successfully tested this in mouse and monkey models and have licensed the technology to a biotech company that plans to test it in humans in two years. We are very excited to see if this can develop into an effective ASD therapy.”
Because most ASD cases involve the less severe, but more complex polygenic variety, a single gene fix will not solve the problem. In these cases, Feng is exploring cellular- rather than genomic-level solutions.
“With our ongoing research into neural circuit mechanisms, we should soon be able to modulate the circuits by developing a drug that can relatively specifically act upon them,” says Feng. “If it works, we will reduce repetitive behavior in many ASD types, and possibly also in OCD and Tourette syndrome.”
Feng is also exploring another therapeutic approach. “We may be able to inject a non-toxic virus into the brain that carries a protein designed to control neuronal activity,” says Feng. “You could take a pill that would activate the protein to control the circuit function and thus the symptom. Some of these techniques will likely be tested in the clinic in the next few years.”
In addition to his biomedical research, Feng’s team is developing minimally invasive tools to study the brain. “The brain is complex and you cannot easily open up the skull and see every details, which makes it difficult to study.”
Feng’s lab uses a variety of techniques to understand the roles of synaptic proteins in the postsynaptic complex. These molecular genetic approaches include slice and in vivo physiology, calcium imaging, transcriptome analysis, proteomic analysis, in vitro screening, transgenic animals, and regional and cell type-specific knockout.
Single-cell RNA sequencing dramatically reduces the cost and increases the data, which you can use to compare cells from normal and patient brains.
Recent developments in single-cell RNA sequencing have been especially useful. “The ability to track each cell and identify all genes expressed in it using a unique barcode allows us to sequence millions of cells at once,” says Feng. “Single-cell RNA sequencing dramatically reduces the cost and increases the data, which you can use to compare cells from normal and patient brains. In animals, you can trace how a disease progresses, what cell types are affected, and what kind of gene expression changes. With a greater understanding of the progression of a disease, we can potentially find ways to intervene earlier or prevent it.”
Feng also employs minimally invasive tools for neural manipulation using chemogenetics and optogenetics. “With chemogenetics, you mutate a desired protein, send it to any target neuron, and administer a drug to activate it,” says Feng. “Chemogenetics is very minimally invasive, and it affects the neuron for a long time. However, because you need to wait for the drug to reach the brain, it is not very suitable for studying precise actions of the neuron or rapidly changing short-term behavior.”
With optogenetics, instead of targeting neurons with a drug, you introduce a light-sensitive protein that attaches to the target. “When you shed light on the neuron, the neuron will be excited or inhibited depending on which optogenetic tools you use,” says Feng. “In this way you can manipulate the function of neurons and circuits of neurons very precisely. Optogenetics is very powerful for neurologic research because its millisecond precision can keep up with a neuron’s millisecond scale firing rate.”
Optogenetics and chemogenetics are now widely used in animal models for research, and chemogenetics has begun to move into pre-clinical testing for treating depression and Parkinson's disease. Optogenetics has yet to make that leap, however, due to the invasive nature of inserting optic fiber into the brain.
“Light has difficulty penetrating dense brain tissue, and is blocked by the skull,” says Feng. “Optogenetics has required sticking the fiber into the brain, which is very invasive.”
In 2020, Feng’s lab announced an optogenetics technique that is more sensitive to light, allowing the light source to be placed outside a mouse skull. “We knew that if we could make the optogenetics very sensitive, then we would not need to insert an optic fiber into the brain,” says Feng.
Working from existing research into light sensitive proteins called opsins, Feng combined two opsin mutations to create an ultra-light sensitive opsin called SOUL. The new opsin is not only more sensitive but can stay active longer after light exposure.
“Now, at least in mice, you don't need to insert optic fiber into the brain,” says Feng. “You can shed light outside the skull and activate any region in the mouse brain. In larger animals such as monkeys and humans, the skull is thicker, so you still need to insert the optics inside the skull. But for the first time, you do not need to penetrate the dura, the thick membrane that protects the brain. In this way, we can use a larger light source to activate many brain regions in large animals.”
Using SOUL-based optogenetics, Feng’s lab has made some interesting discoveries about brain waves, the other major neural communications medium aside from synaptic transmissions. Brain waves, which are typically monitored by EEG electrodes placed on the skull, involve many different neurons working in unison to create rhythmic activity. Whereas synapses fire at the millisecond level, brain waves use slower rhythmic communications based on neuronal membrane potential oscillations.
Using SOUL optogenetics, Feng was able to reversibly generate brain waves by activating many neurons at once via light stimulation. “EEG studies have shown that specific brain wave changes are linked to certain cognitive disorders,” says Feng. “But because there was no way to modulate the waves, it was hard to show a causative link. Now, using optogenetics on animal models, we have been able to generate or disrupt the waves to determine cause and effect.”
In his latest research, Feng is exploring the neurologic causes of the complex cognitive behaviors found in schizophrenia and depression. Over the last decade, large scale genetic sequencing has revealed many genes that significantly contribute to schizophrenia. Recently, labs at MIT, Broad Institute, and Harvard have generated animal models based on the new genetic discoveries.
“Using these animal models, we can now start to understand what changes at the cellular and molecular levels create the changes at the circuits level,” says Feng. “We should be able to identify targets in humanized mouse models that can improve the cognitive dysfunction in schizophrenia.”
Depression, which is on the rise and now affects around 10 percent of the population, poses a different problem. “Most therapeutic treatments for depression are not very effective, and depression is much less genetic, which makes it difficult to use genetics-based models,” says Feng. “Instead, we study neural circuit dysfunction to search for a way to induce depression-like behavior for a short time. I'm really excited by the prospect that in five years we may have new therapeutic strategies and new druggable targets for depression.”