Palaguachi, F. | bioRxiv Science

bioRxiv2022

Astrocytes regulate spatial memory in a sex-specific manner

Cognitive processes and neurocognitive disorders are regulated by astrocytes and have prominent sex differences. However, the contribution of astrocytes to sex differences is not known. We leveraged astrocyte-targeted gene editing and chemogenetics in adult mice to reveal that astrocytic glutamate receptors and other G protein-coupled receptors (GPCRs) modulate hippocampus-dependent cognitive function in a sexually dimorphic manner. In females, spatial memory was improved by increasing metabotropic glutamate receptor 3 (mGluR3) in astrocytes or stimulating astrocytic Gi/o-coupled signaling, whereas stimulating Gs-coupled signaling impaired memory. However, in males, memory was improved by reducing mGluR3 or stimulating Gs-coupled signaling, whereas stimulating Gi/o-coupled signaling impaired memory. Thus, memory requires a sex-specific balance of astrocytic Gs-coupled and Gi/o-coupled receptor activities, and disease-associated alterations or therapeutic targeting of these pathways may cause opposing sex-dependent effects on cognitive function. SummaryGlia cause sex-specific changes in cognition

neuroscience↗

bioRxiv2022

Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines

TDP-43 pathology is prevalent in dementia but the cell type-specific effects of TDP-43 are not clear and therapeutic strategies to alleviate TDP-43-linked cognitive decline are lacking. We found that patients with Alzheimers disease (AD) or frontotemporal dementia (FTD) have aberrant TDP-43 accumulation in hippocampal astrocytes. In mouse models, induction of widespread or hippocampus-targeted accumulation in astrocytic TDP-43 caused progressive memory loss and localized changes in antiviral gene expression. These changes were cell-autonomous and correlated with impaired astrocytic defense against infectious viruses. Among the changes, astrocytes had elevated levels of interferon-inducible chemokines and neurons had elevated levels of the corresponding chemokine receptor CXCR3 in presynaptic terminals. CXCR3 stimulation altered presynaptic function and promoted neuronal hyperexcitability, akin to the effects of astrocytic TDP-43, and blockade of CXCR3 reduced this activity. Ablation of CXCR3 also prevented TDP-43-linked memory loss. Thus, astrocytic TDP-43 dysfunction contributes to cognitive impairment through aberrant chemokine-mediated astrocytic-neuronal interactions. SummaryIn dementia, protein buildup in glia enhances chemokine signaling to synapses and impairs specific aspects of neurocognitive function.

neuroscience↗