Astrocyte-synapse structural plasticity in neurodegenerative and neuropsychiatric diseases.

Synaptic dysfunction is a common feature across a broad spectrum of brain diseases, spanning from psychopathologies such as post-traumatic stress disorder (PTSD) and substance use disorders (SUD) to neurodegenerative diseases like Alzheimer's and Parkinson's disease (AD and PD). While neuroscience research aiming to understand the mechanisms underlying synaptic dysfunction has traditionally focused on the neuronal elements of the synapse, recent research increasingly acknowledges the contribution of astrocytes as a third element controlling synaptic transmission. This also sparked interest to investigate the tripartite synapse and its role in the etiology of neurological diseases. According to recent evidence, changes in the structural interaction between astrocytes and synapses not only play a pivotal role in modulating synaptic function and behavioral states, but are also implicated in the initiation and progression of various brain diseases. This review aims to integrate recent findings that provide insight into the molecular mechanisms underpinning astrocytic structural changes at the synapse. We offer a comprehensive discussion of the potential implications of compromised astrocyte-synapse interactions, and put forward that astrocytic synaptic coverage is generally reduced in numerous neurological disorders, with the extent of it being disease- and stage- specific. Finally, we propose outstanding questions on astrocyte-synapse structural plasticity that are relevant for future therapeutic strategies to tackle neurodegenerative and neuropsychiatric diseases.