Regulation of astrocyte maturation and synapse development by PTPRZ1

Astrocytes are structurally and functionally complex glial cells capable of exerting dynamic control over synapse development and maturation through direct interactions with thousands of neuronal synapses. Atypical astrocyte structure and function is a recurring phenotype in neurological disorders concurrently characterized by dysregulated synaptic function, including autism spectrum disorder, epilepsy, and Schizophrenia. Unfortunately, we lack a complete understanding of astrocyte cell biology, posing a significant barrier to understanding how astrocyte dysfunction might initiate or exacerbate disease-related synaptic dysregulation. To address this knowledge gap, we performed a reverse genetic screen to identify novel regulators of astrocyte development and identified protein tyrosine phosphatase receptor Z1 (PTPRZ1) as a significant regulator of astrocyte morphogenesis in vitro. PTPRZ1 plays important roles in numerous neurodevelopmental processes and is highly expressed in astrocytes during brain development; however, the astrocyte-specific function of PTPRZ1 is unknown. To investigate the astrocyte-specific function of PTPRZ1 in vivo, we developed a Ptprz1 conditional knockout mouse to delete Ptprz1 from postnatal astrocytes and found a significant decrease in excitatory synapse density in the visual cortex. We also observed abnormal perineuronal net (PNN) structure, suggesting a potential role for PTPRZ1 in cortical plasticity. Here, we propose a detailed investigation of the astrocyte-specific role of PTPRZ1 in cortical development to test the central hypothesis that astrocyte-derived PTPRZ1 is a critical regulator of both synapse development and cortical plasticity. In Aim 1, we will expand upon our recent work to define the primary mechanism through which astrocytic PTPRZ1 regulates excitatory synapse development. This will generate new insight into the underlying mechanisms of astrocyte regulation of excitatory synapse development. In Aim 2, we will investigate the role of astrocytic PTPRZ1 in regulating PNN structural formation and cortical plasticity. Notably, these experiments will characterize astrocyte-PNN and astrocyte-PNN- synapse interactions in unprecedented detail by developing a robust, scalable, multivariate image acquisition and analysis pipeline under the mentorship of microscopy and bioinformatic experts at UNC-Chapel Hill. Overall, the proposed work will significantly advance our foundational understanding of the regulatory role astrocytic PTPRZ1 plays in synapse development and cortical plasticity, while identifying potential mechanisms underlying disease-relevant phenotypes. The exceptionally collaborative training environment at UNC-Chapel Hill will enable multiple training opportunities across core facilities and within the co-sponsor's lab. The implementation of in vitro quantitative proteomics, advanced super-resolution microscopy, multivariate image analysis, and the ocular dominance plasticity assay will provide balanced and comprehensive training for the applicant to expand their technical skillset and grow as an independent neuroscientist. Project Number: 1F31NS145447-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Hayli Spence-Osorio | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $44,404 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F03A-V (21)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11385796