P2.02. ASTROCYTE-DERIVED SYNAPTIC PROTEINS MEDIATE STRESS-INDUCED BEHAVIORAL CHANGES AND MODULATE ANTIDEPRESSANT RESPONSES IN MICE.
Anna M. Lech1, Bartosz Zglinicki1, Patrycja Ziuzia1,2, Martyna Skuła1,3, Michał Ślęzak1
1 Lukasiewicz Research Network – PORT Polish Center for Technology Development, Stablowicka 147 St., Wroclaw, Poland
2 Wroclaw University of Environmental and Life Sciences, Norwida 25 St., Wroclaw, Poland
3 Wroclaw University of Science and Technology, 27 Wybrzeże Stanisława Wyspiańskiego St., Wroclaw, Poland
INTRODUCTION: Depression is one of the most prevalent mental health conditions worldwide, characterized by a diverse range of clinical symptoms, including impaired emotional regulation, social interactions and decision-making. While extensive evidence implicates disturbed synaptic homeostasis in the pathophysiology of depression, the role of astroglia in regulating plastic changes of neural networks in the adult brain remains underexplored. We previously found that chronic stress induces profound changes in transcriptomic profile of prefrontal cortex (PFC) astrocytes, which were mediated by glucocorticoid receptor (GR). Among stress-regulated genes were astrocyte-specific factors involved in synapse formation and elimination.
AIM(S): Here, we investigated how manipulation of genes controlling synapse number influences behavioral effects of chronic stress and how these genes contribute to antidepressant action.
METHOD(S): To achieve astrocyte-specific protein silencing in the mPFC, we bilaterally injected mice with shRNA-GFP vectors targeting each gene. Behavioral phenotyping was conducted using a system for tracking freely moving mice cohorts. Chronic corticosterone (CORT, 21 days in drinking water) was used to induce depressive-like behavior. We assessed individual and social behaviors in both sexes during three sessions: 3 weeks post-vector injection, post-stress, and 24h after a single subanesthetic ketamine dose. Immunostaining for GFP and astrocyte markers validated silencing efficacy and distribution.
RESULTS: Principal Component Analysis (PCA) of behavioral traits revealed that silencing of specific astrocytic proteins distinctly altered the behavior of animals following chronic CORT and ketamine exposure. We further identified the behavioral variables contributing most to the observed variance in PCA.
CONCLUSIONS: These findings underscore the pivotal role of astrocyte-derived synaptic proteins in GR-dependent stress mechanisms, advancing our understanding of how astroglia modulate neural circuits in depression.
FINANCIAL SUPPORT: OPUS 2021/41/B/NZ3/04099; Horizon Europe SAME-NeuroID:101079181