ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2023
Microglial P2Y12 mediates chronic stress-induced synapse loss in the prefrontal cortex and associated behavioral consequences.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 46 citations in OpenAlex.
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- Clopidogrel Administration Impairs Neurovascular Unit Recovery and Exacerbates Amyloid Beta Accumulation in Aged Mice Post-Stroke.International journal of molecular sciences · 2026Article
- Synaptic remodeling and the female depression exposome: a mini-review of neuroendocrine, epigenetic, and social determinants.Frontiers in neuroscience · 2026Review
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- Maladaptive Neuroplasticity Under Stress: Insights into Neuronal and Synaptic Changes in the Prefrontal Cortex.Molecular neurobiology · 2025Review
- Early Life Injury Alters Spinal Astrocyte Development.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Stress-induced dysfunction of neurovascular astrocytes in the prefrontal cortex contributes to sex-dependent deficits in cognition and behavior.Molecular psychiatry · 2025Article
- Characterizing Microglial Morphology: Methodological Advances in Confocal Imaging and Analysis.Cells · 2025Article
- Sensory neurostimulation promotes stress resilience with frequency-specificity.bioRxiv : the preprint server for biology · 2025Article
- Review
- Hormonal contraceptives in adolescence impact the neuroimmune environment of the medial prefrontal cortex and hippocampus in female rats.Brain, behavior, and immunity · 2025Article
- The evolving neurobiology of early-life stress.Neuron · 2025Review
- Luteolin ameliorates chronic stress-induced depressive-like behaviors in mice by promoting the Arginase-1Acta pharmacologica Sinica · 2025Article
- Global trends of purinergic receptors and depression: A bibliometric analysis from 2003 to 2023.World journal of psychiatry · 2025Article
- Microglial type I interferon signaling mediates chronic stress-induced synapse loss and social behavior deficits.Molecular psychiatry · 2025Article
- Biological sex, microglial signaling pathways, and radiation exposure shape cortical proteomic profiles and behavior in mice.Brain, behavior, & immunity - health · 2025Article
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Authors and funding
6 authors at 1 institution in 1 country.
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Abstract
Chronic unpredictable stress (CUS) drives microglia-mediated neuronal remodeling and synapse loss in the prefrontal cortex (PFC), contributing to deficits in cognition and behavior. However, it remains unclear what mechanisms guide microglia-neuron interactions in stress. Evidence indicates that neuronal activity-dependent purinergic signaling directs microglial processes and synaptic engagement via P2Y12, a purinergic receptor exclusively expressed by microglia in the brain. Stress alters excitatory neurotransmission in the PFC, thus we aimed to determine if P2Y12 signaling promotes functional changes in microglia in chronic stress. Here we used genetic ablation of P2Y12 (P2ry12-/-) or pharmacological blockade (clopidogrel, ticagrelor) to examine the role of purinergic signaling in stress-induced microglia-neuron interaction. Multiple behavioral, physiological, and cytometric endpoints were analyzed. Deletion of P2Y12 led to a number of fundamental alterations in the PFC, including the heightened microglial number and increased dendritic spine density. Flow cytometry revealed that microglia in P2ry12-/- mice had shifts in surface levels of CX3CR1, CSF1R, and CD11b, suggesting changes in synaptic engagement and phagocytosis in the PFC. In line with this, pharmacological blockade of P2Y12 prevented CUS-induced increases in the proportion of microglia with neuronal inclusions, limited dendritic spine loss in the PFC, and attenuated alterations in stress coping behavior and working memory function. Overall, these findings indicate that microglial P2Y12 is a critical mediator of stress-induced synapse loss in the PFC and subsequent behavioral deficits.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.