UCLA researchers in the Department of Physiology have identified specific endogenous receptors that activate an astrocyte signaling pathway, which is beneficial for restoring astrocyte morphology and ameliorating phenotypes associated with obsessive-compulsive disorder and other brain disorders.
BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric disorder characterized by obsessive thoughts and repetitive behaviors, which are often linked to dysfunction in cortical-striatal neural circuits. Astrocytes, a predominant type of glial cell, are significantly implicated in various brain disorders including OCD, due to their crucial roles in maintaining neuronal health and circuit function. The complex morphology of astrocytes is compromised in disease settings, leading to disrupted tissue homeostasis and impaired cell-cell signaling across the central nervous system. Hence, targeting the restoration of astrocyte morphology presents a promising therapeutic strategy for treating OCD and other several other diseases that possess astrocytes with reduced morphology (e.g., Alzheimer’s disease, Huntington’s disease).
INNOVATION: Researchers at UCLA led by Dr. Baljit Khakh have discovered an astrocyte signaling pathway that plays a crucial role in correcting astrocyte morphology and is directly linked to the repetitive and compulsive behaviors typical of OCD. They have pinpointed cell-selective and region-enriched endogenous receptors that activate this advantageous pathway, effectively mitigating repetitive behaviors and anxieties. In mouse models of OCD, astrocyte-specific treatments have demonstrated molecular, cellular, and behavioral improvements by restoring astrocyte morphology and critical mechanisms such as tissue homeostasis. These findings align with human gene expression data, suggesting promising therapeutic potential for brain disorders.
POTENTIAL APPLICATIONS:
ADVANTAGES:
DEVELOPMENT-TO-DATE: Proof of concept shown in mice that are models of OCD and Alzheimer’s disease
Related papers (from the inventors only):
1. Soto, Joselyn S., et al. "In vivo identification of astrocyte and neuron subproteomes by proximity-dependent biotinylation." Nature Protocols 19.3 (2024): 896-927.
2. Soto, Joselyn S., et al. "Astrocyte–neuron subproteomes and obsessive–compulsive disorder mechanisms." Nature 616.7958 (2023): 764-773.
3. Endo, Fumito, et al. "Molecular basis of astrocyte diversity and morphology across the CNS in health and disease." Science 378.6619 (2022): eadc9020.
4. Soto, Joselyn S., et al. “Astrocyte Gi-GPCR signaling corrects compulsive-like grooming and anxiety-related behaviors in Sapap3 knockout mice.” Neuron. 2024 Oct 23;112(20):3412-3423.
KEYWORDS: Astrocyte, endogenous receptors, signaling pathway, proteomics, morphology, obsessive-compulsive disorder, brain, neuron, neuropsychiatric disorder, repetitive behavior, anxiety, OCD, CNS, and Alzheimer’s disease