id_1012. HIGH-THROUGHPUT BEHAVIOR ANALYSIS REVEALS SEX-SPECIFIC CONTRIBUTION OF ASTROCYTE-DERIVED FACTORS TO EFFECTS OF CHRONIC CORTICOSTERONE AND KETAMINE IN MICE
Anna M. Lech1, Patrycja Ziuzia1,2, Bartosz Zglinicki1, Martyna Skuła1,3, Klaudia Kuzdrowska1, Michał Ślęzak1
1 P4Health, Lukasiewicz Research Network – PORT Polish Center for Technology Development, Wroclaw, Poland
2 Department of Biochemistry and Molecular Biology, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
3 Department of Artificial Intelligence, Wroclaw University of Science and Technology, Wroclaw, Poland
INTRODUCTION: Impaired synaptic homeostasis is a well-established feature of pathophysiology of psychiatric conditions. These deficits may originate in neurons, but glial cells are also known to mediate multiple aspects of synapse formation and elimination. Our earlier transcriptional profiling revealed crucial role of glucocorticoid receptor-dependent gene network in shaping the molecular profile of astrocytes in human depression and mouse chronic stress. One class of genes were astrocyte-specific synaptogenic factors. However, the contribution of specific proteins to plasticity of adult neural circuits and their potential as therapeutic targets remain unexplored.
AIM(S): The present work investigates how targeted manipulation of selected astrocyte proteins controlling synapse number shapes behavioral consequences of chronic stress and the response to antidepressant treatment.
METHOD(S): Gene silencing in medial prefrontal cortex was achieved through bilateral delivery of shRNA vectors containing a GFP reporter. Behavioral assessment of freely moving mice captured both, individual parameters – such as locomotion and speed movement, and social behaviors. A chronic corticosterone paradigm (CORT, 21 days in drinking water) was used to permanently activate the GR signaling. We quantified behavioral parameters in males and females across three time-points: baseline, after completion of CORT treatment, and 24h following a single subanesthetic dose of ketamine.
RESULTS: Immunostaining of GFP and astrocyte-specific markers confirmed the localization and the efficacy of gene knockdown. Principal Component Analysis (PCA) revealed that distinct behavioral components contributed to sex-specific effects of chronic CORT and ketamine.
CONCLUSIONS: These findings underscore the importance of astrocyte-derived synaptic regulators in glucocorticoid-dependent responses and advance our understanding of how glia shapes neural circuits in depression.
FINANCIAL SUPPORT: This research was funded by National Science Center grant number OPUS2021/41/B/NZ3/04099