Biology subjects

Salas, I. H.

Publications and source records attributed to Salas, I. H..

2 recordsLinked to original sources

bioRxiv2024

Astrocyte transcriptomic analysis identifies glypican 5 downregulation as a contributor to synaptic dysfunction in Alzheimer disease models

Synaptic dysfunction is an early feature in Alzheimers disease (AD) and correlates with cognitive decline. Astrocytes are essential regulators of synapses, impacting synapse formation, maturation, elimination and function. To understand if synapse-supportive functions of astrocytes are altered in AD, we used astrocyte BacTRAP mice to generate a comprehensive dataset of hippocampal astrocyte transcriptional alterations in two mouse models of Alzheimers pathology (APPswe/PS1dE9 and Tau P301S), characterizing sex and age-dependent changes. We found that astrocytes from both models downregulate genes important for synapse regulation and function such as the synapse-maturation factor Glypican 5. This transcriptional signature is shared with human post-mortem AD patients. Manipulating a key component of this signature by in vivo overexpression of Glypican 5 in astrocytes is sufficient to prevent early synaptic dysfunction and improve spatial learning in APPswe/PS1dE9 mice. These findings open new avenues to target astrocytic factors to mitigate AD synaptic dysfunction.

neuroscience↗

bioRxiv2023

Astrocyte glypican 5 regulates synapse maturation and stabilization

The maturation and stabilization of appropriate synaptic connections is a vital step in the development of neuronal circuits, however the molecular signals underlying these processes are not fully understood. We show that astrocytes, through production of glypican 5 (GPC5), are required for maturation and refinement of synapses in the developing mouse cortex. In the absence of astrocyte GPC5 thalamocortical synapses in the visual cortex show structural immaturity during the critical period, including smaller presynaptic terminals, decreased postsynaptic density area, and presence of more postsynaptic partners at multisynaptic connections. This structural immaturity is accompanied by a delay in developmental incorporation of GLUA2-containing calcium impermeable AMPARs at intracortical synapses. The functional impact of this is that mice lacking astrocyte GPC5 exhibit increased levels of ocular dominance plasticity in adulthood. This shows astrocyte GPC5 is necessary for maturation and stabilization of synaptic connections in typical development, with implications for understanding disorders with altered synaptic function, including Alzheimers disease, where GPC5 levels are altered.

neuroscience↗