Adult Mouse Leptomeninges Exhibit Regional and Age-related Cellular Heterogeneity Implicating Mental Disorders

Transplantation of retinal pigment epithelial (RPE) cells holds great promise for RPE tissue repair in patients with retinal degenerative diseases, such as age-related macular The leptomeninges envelop the central nervous system (CNS) and contribute to cerebrospinal fluid (CSF) production and homeostasis. We analyzed the meninges overlying the anterior or posterior forebrain in the adult mouse by single nuclear RNA-sequencing (snucRNA-seq). This revealed regional differences in fibroblast and endothelial cell composition and gene expression. Surprisingly, these non-neuronal cells co-expressed genes implicated in neural functions. The regional differences changed with aging, from 3 to 18 months. Cytokine analysis revealed specific soluble factor production from anterior vs posterior meninges that also altered with age. Secreted factors from the leptomeninges from different regions and ages differentially impacted the survival of anterior or posterior cortical neuronal subsets, neuron morphology, and glia proliferation. These findings suggest that meningeal dysfunction in different brain regions could contribute to specific neural pathologies. The disease-associations of meningeal cell genes differentially expressed with region and age were significantly enriched for mental and substance abuse disorders. Anterior and posterior leptomeninges tissues were isolated from six young (3 months) and six old (18 months) mice. Tissue lysis and nuclei isolation were performed and single cell library preparation was performed using the SMART-Seq ICELL8 Application Kit.