Astrocyte-derived PTPRZ1 regulates excitatory synapse density in the mouse cortex

Protein tyrosine phosphatase receptor type Z1 (PTPRZ1) is one of the most abundantly expressed and enriched genes in astrocytes during development, yet its function in astrocytes is unknown. Using an astrocyte-neuron co-culture system, we found that knockdown of Ptprz1 in astrocytes significantly impaired astrocyte branching morphogenesis. To investigate the function of PTPRZ1 in astrocytes during brain development, we generated a Ptprz1 conditional knockout mouse and deleted Ptprz1 from astrocytes postnatally, after the bulk of astrogenesis is complete. At postnatal day 21, we found subtle changes in astrocyte morphology and a reduction in the density of co-localized pre and post synaptic excitatory synapse markers across multiple layers of the visual cortex in both male and female mice, suggesting important functions for astrocytic PTPRZ1 in both astrocyte morphogenesis and synaptogenesis. PTPRZ1 is expressed in several neural cell types, including radial glial stem cells and oligodendrocyte progenitor cells (OPCs), and regulates critical aspects of neurodevelopment, including neurite outgrowth, neuronal differentiation, myelination, and extracellular matrix (ECM) development. Moreover, altered PTPRZ1 expression is associated with schizophrenia and glioblastoma. Therefore, this mouse model is a valuable resource for investigating cell-type-specific PTPRZ1 function in numerous neurodevelopmental and neuropathological mechanisms. Significance Statement PTPRZ1 is an abundant, astrocyte-enriched protein linked to neurological dysfunction; however, its astrocyte-specific functions are unknown. We generated a Ptprz1 conditional knockout mouse and found that astrocyte-specific deletion of Ptprz1 reduces the density of co-localized excitatory synapse markers in the developing mouse cortex, with mild impact to astrocyte morphology. PTPRZ1 is an emerging therapeutic target for glioblastoma and neurodegeneration. This study provides a new tool to study PTPRZ1 function in neurodevelopment and neuropathology.