A dynamic duo: uncovering the Dual Role of Astrocytes and Neurons in OCD Pathogenesis
By Pranav Suraparaju
This article by the Khakh lab at UCLA presents a new aspect of obsessive-compulsive disorder (OCD) research by focusing on the interactions between two types of brain cells: astrocytes and neurons. Astrocytes support and protect neurons, which are the main cells for sending signals in the brain. This research team used advanced methods to study proteins in these cells and found something interesting: SAPAP3, a protein linked to OCD, was found in astrocytes. Before this, scientists thought this protein was only in neurons. This discovery is a big deal because it shows us that astrocytes might also play a role in OCD. Mice deficient in SAPAP3 obsessively groom themselves, and delivering the SAPAP3 paper back to neurons and astrocytes rescued this behavior. However, only neuronal rescue of the protein reduced anxiety in the mice. This result highlights that we still have much to learn about how neurons and astrocytes cooperate together in the healthy brain and in anxious states. This research opens up new paths for understanding OCD and suggests that future treatments should include both neurons and astrocytes. The methodology in this paper particularly is a step forward in finding better ways to help people with OCD, even if it raises questions about the exact role of astrocytes.
Methods: In this study, their major technological advance was similar to the implementation of proximity protein labeling, specifically proximity-dependent biotinylation. A protocol paper further explains this technique. It involves the use of an enzyme, typically biotin ligase (think of this as a tiny molecular “tagger” that goes around sticking biotin tags onto proteins that are close by), in this case they used an engineered version known as the BioID2 system, to study astrocytes and neurons within the central nervous system. Unlike standard methods that rely on cell dissociation and sorting, which can lead to significant loss of the cell’s shape and important internal cell compartments, their approach allowed for tagging of proteins inside living cells in specific areas and parts of the cell. This was achieved by expressing the biotin ligase BioID2 selectively in either astrocytes or neurons. The BioID2 system facilitated the labeling of proteins very close to the enzyme within a radius of approximately 10 nanometers, enabling them to map the protein interactions and modifications within these brain cells with remarkable specificity and detail. To visualize and analyze these protein interactions, they utilized genetically modified viruses to introduce the BioID2 system into specific cell populations. This technique provided them with the capability to observe changes in cell behavior or function in response to the introduced genes. Furthermore, they used advanced imaging techniques to examine the cells and their components at a microscopic level, providing information into the cellular processes at work. Their approach marked a shift from traditional methods by preserving the cell’s shape and structure. This facilitated a more accurate analysis of protein interactions and functions within the cell’s normal environment. Through these carefully designed methods, their study aimed to reveal the detailed mechanisms that regulate cell function and disease, making these complex scientific ideas easier to understand.
Results & Discussion: The study revealed that both astrocytes and neurons express SAPAP3, a protein involved in synaptic organization and function, linked to the regulation of neural circuits and associated with Obsessive-Compulsive Disorder (OCD) when dysregulated. Utilizing genetic tools, researchers introduced a protein marker into mice to investigate protein interactions within these brain cells. Interestingly, they discovered distinct protein networks in astrocytes and neurons, which were affected by the presence or absence of SAPAP3. In astrocytes, SAPAP3 was involved in regulating glutamate uptake and the structure of the cell's skeleton, crucial for maintaining cell shape and function. In neurons, SAPAP3 interacts with proteins at the synapse, the junction where neurons communicate. Behavioral experiments showed that reintroducing SAPAP3 into either astrocytes or neurons of SAPAP3-deficient mice rescued OCD-like behaviors, although some behaviors were only able to be rescued by neuronal expression. This study shifts the neuron-centric view of OCD, creating a connection between neurons and astrocytes in the disorder.
Implications and Connection to Literature: This research presents the role of both astrocyte and neurons in the understanding and potential treatment of Obsessive-Compulsive Disorder (OCD). Traditionally viewed as a problem originating from faulty neuron signaling in the brain, this study, along with others like the one by Welch et al. (2007) in Nature Neuroscience, broadens our perspective by showing that SAPAP3 is also vital in astrocytes for brain health. Similarly, previous research demonstrated that mice genetically modified to lack the SAPAP3 gene exhibited OCD-like behaviors including compulsive grooming leading to bald patches and these behaviors were enhanced when the gene was reintroduced into the striatum, showing its significance in the neural pathways implicated in OCD (Feng et al., 2007, Nature) This finding supports the idea that OCD involves complex interactions among various types of brain cells, not just neurons. By showing that SAPAP3 in astrocytes can alter OCD-related behavior, this study creates new treatment paths that could target both neurons and astrocytes.
How does this connect to humans? This research ended by directly asking about connection to human Obsessive Compulsive Disorder (OCD) by looking at the changes in protein levels in mice that are genetically modified to lack SAPAP3. The study identified 66 proteins that differed between normal mice and those with SAPAP3, many of which are connected with genes that are already known to behave differently in humans with OCD. This suggests a connection between the animal model and human condition, indicating that disruptions in SAPAP3 not only affects mouse behavior in ways that resemble OCD but it might also affect similar issues in humans. Furthermore, the study looked into genes that were associated with repetitive behaviors, a crucial aspect of OCD, finding that most of these genes are active in both astrocytes and neurons. By connecting protein changes in mouse brains and gene expression patterns in human OCD patients, this study strengthens its argument that the mechanisms discovered in mice could offer clues to understanding and treating OCD in humans, ultimately promising new ways to develop therapies that target these shared biological pathways.
Future Research and Limitations: The findings from this study not only shows the biology behind Obsessive-Compulsive Disorder (OCD) but also creates the way for impactful future research. By demonstrating the critical role of the SAPAP3 protein in both astrocytes and neurons, this research challenges the neuron-centric view of OCD and creates an inclusive approach to understanding brain disorders. Future research can build on this by understanding how SAPAP3 functions in astrocytes versus neurons, and how deficiencies in one or both cell types lead to OCD like behaviors. Additionally, the observed differences in SAPAP3 expression between astrocytes and neurons during development show the importance of the need to pay attention to when and where genes are active in understanding how diseases start and evolve. This opens new ideas for research specifically into how changes in brain cell communication contribute to OCD and similar neuropsychiatric conditions from the developmental stage through adulthood. Ultimately, this research emphasizes the need for a comprehensive approach to the science of the brain specifically focusing on how different cell types and their molecular processes interact in order for us to understand and address complex mental health conditions.
Summary of the findings and technical advances from this paper.