Research in mouse models suggest that astrocytes, a type of cell usually characterized as the brain’s support system, may play an important role in obsessive-compulsive disorder (OCD)-related behaviors. Studying the proteins expressed in mice by neurons and astrocytes in the brain’s striatum, the University of California, Los Angeles (UCLA) scientists found that a protein in neurons called SAPAP3—which is associated with OCD and repetitive behaviors—was also found in the star-shaped astrocytes. The new clue about the brain mechanisms behind OCD, a disorder that is incompletely understood, came as a surprise to the researchers. They had originally sought to study how neurons interact with astrocytes, which are known to provide support and protection to neurons.
The new discovery might point to new therapeutic strategies that target both astrocytes and neurons, for OCD and potentially other brain disorders. “Our research has revealed a new cellular mechanism, which not only involves neurons—something we already knew— but also involves astrocytes, working together,” said Baljit Khakh, PhD, a professor of physiology and neurobiology at the David Geffen School of Medicine at UCLA. “Now we could expand our research in this area to cover additional mechanisms and cells.” Khakh is corresponding author of the team’s work, which is published in Nature and titled “Astrocyte-neuron subproteomes and obsessive-compulsive disorder mechanisms.”
OCD, a chronic anxiety disorder characterized by repetitive thoughts and actions, affects an estimated 2–3% of the U.S. population in their lifetimes, though its prevalence may be higher due to underreporting and underdiagnosis. “OCD is characterized by obsessive intrusive thoughts, compulsions manifested as repetitive behaviours and anxiety,” the authors noted. Psychotherapy, antidepressant drugs, or both are typically prescribed for OCD, but available treatment is ineffective for a sizable share of patients. However, the investigators continued, the disorder is “incompletely understood and poorly treated.”
Astrocytes are vital components of the brain and, like neurons, they display morphologies and properties that differ among the different brain regions, the authors continued. And while both astrocytes and neurons are implicated in brain diseases, including psychiatric disorders, “little is known about shared or separate astrocytic and neuronal molecular mechanisms and their respective contributions within brain regions relevant to defined psychiatric diseases or phenotypes in mice,” they wrote.
A part of the brain known as the striatum, which is involved in decision making and motor control, is thought to play a key role in OCD. “Classically considered a neuronal disease, OCD involves striatal circuit malfunction, but the molecular and cellular basis of the disorder has remained unclear,” the team continued. It is this area of the brain that the UCLA researchers studied when they sought to examine the interactions between astrocytes and neurons.
Khakh is among the researchers in recent years who have extensively studied astrocytes, thanks to technological advances that have made it more feasible to study these complex cells. Scientists are still trying to understand the apparent role that these cells may play in psychiatric and neurodegenerative diseases.
While previous research has compared gene expression between neurons and astrocytes, the newly reported study analyzed protein expression, providing new insights into the apparent interplay between the two cell types. “In the settings of physiology and disease, most studies have compared astrocytes and neurons using neuropathological methods, physiology, cellular markers or RNA expression analyses,” the team explained. However, they pointed out, while such RNA studies are “invaluable”, the relationship between RNA expression levels and protein levels is highly complex, and so “it is crucial to identify specific protein-based mechanisms for neurons and astrocyte.”
Study co-author Joselyn Soto, a neuroscience PhD student at UCLA’s medical school, added, “We really have to look at the proteins because they are very complex and diverse. Depending on which cell expresses which proteins, we can predict the functions of that cell.”
For their reported work the researchers used multiple approaches to isolate and visualize proteins across neurons and astrocytes within the striatum, and within different subcellular compartments of the astrocytes. “We evaluated cytosolic and plasma membrane compartments for astrocytes and neurons to discover how these cells differ at the protein level in their signalling machinery. We also assessed subcellular compartments of astrocytes, including end feet and fine processes, to reveal their subproteomes and the molecular basis of essential astrocyte signalling and homeostatic functions.”
When the team compared proteins found in neurons and in astrocytes, they unexpectedly discovered that both cell types contained the protein SAPAP3, which is associated with OCD. “Notably, SAPAP3 (encoded by Dlgap3), which is associated with obsessive–compulsive disorder (OCD) and repetitive behaviours, was detected at high levels in striatal astrocytes and was enriched within specific astrocyte subcompartments where it regulated actin cytoskeleton organization,” they commented.
They scientists then carried out studies in a mouse model of OCD in which the SAPAP3 gene is deleted (SAPAP3 knockout (KO) mice). These animals display OCD-like anxiety symptoms, and repetitive self grooming. “SAPAP3 KO mice are relevant models to use because SAPAP3 genetic variations are associated with some forms of human OCD and SAPAP3 is highly expressed in the striatum of humans and mice,” the investigators stated. They developed a method to reintroduce SAPAP3 specifically to astrocytes or neurons, in the SAPAP3 KO mice. The investigators found that the two types of cells interacted in different ways when the protein’s effects on compulsion and anxiety, two of the typical hallmarks of OCD, was evaluated.
The test results showed that the SAPAP3 KO mice no longer compulsively groomed themselves after the SAPAP3 protein was delivered back to astrocytes and neurons, suggesting that both types of cells could be valid targets for treatments aimed at curbing compulsion. However, only neurons with the reintroduced SAPAP3 protein were associated with reduced anxiety in the mice, suggesting that astrocytes would not be a good target for anxiety treatments in OCD. “Our findings underscore molecular, cellular and behavioural similarities as well as differences in regard to astrocytic and neuronal mechanisms relevant to OCD phenotypes in SAPAP3 KO mice,” the investigators stated.
Soto said future research would delve deeper into how the interactions between these cells affect behavior. “These are both major cell types—one doesn’t work without the other … We really wanted to understand how these multicellular interactions within this brain region give rise to these complex behaviors, including compulsion and anxiety.”
Khakh also noted that this new study’s unexpected findings demonstrate the value of pursuing basic biology questions to help form new ideas about the basis of diseases. “This started from a basic question: What proteins make up this complex cell?” he said. “At the outset, we couldn’t have predicted its potential relevance to OCD.” Khakh also acknowledged that more work will be needed to understand even how astrocytes are formed and maintained.
The authors concluded in their paper, “Our proteomics experiments demonstrated how SAPAP3, a protein shared by astrocytes and neurons and involved in human OCD, produces effects on OCD-related behavioural phenotypes through distinct astrocyte and neuron molecular interactions, which, within astrocytes, affect the actin cytoskeleton … Building on recent work with depression and degeneration, our experiments showed that astrocyte and neuron SAPAP3 mechanisms are relevant to OCD phenotypes in mice.”
