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bioRxiv · 10.64898/2025.12.12.693967

Varied monoamine reuptake inhibitors reduce parvalbumin expression; implications for pyramidal cell disinhibition and enhanced neuroplasticity

Hummel, K.·Shautidze, G.·Thorland, E.·Amontree, M.·Wonnenberg, P.·Blanco, I.·Conant, K.
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Abstract

First-line antidepressants are effective in a significant percent of individuals but a full understanding of how these therapeutics target specific endpoints is lacking. Prior work has shown that depression is associated with hippocampal atrophy and that antidepressants can increase neurotrophin levels to increase hippocampal neurogenesis as well as hippocampal pyramidal cell (PC) spine density and arbor. These effects likely contribute to amelioration of symptoms. A less well-explored possibility is that antidepressants concomitantly disinhibit hippocampal PC activity, which could also facilitate increased PC arbor, spinogenesis and/or activity. In accordance, previous studies have shown antidepressants can attenuate stress-induced upregulation of perineuronal nets (PNNs). PNNs are predominantly localized to parvalbumin (PV) expressing GABAergic interneurons and increase PV expression and neuronal activity. Though specific antidepressants have been explored for effects on regional PNN expression, the question of whether hippocampal PNN/ECM remodeling is a shared feature of varied antidepressant drugs and more importantly, of whether it is associated with significant hippocampal PV inhibition, has not been well-addressed. Herein we examine three monoamine reuptake inhibitors, fluoxetine, venlafaxine and viloxazine, in animal models for effects on PNN remodeling and PV expression, a proxy for PV activity. We observe shared effects of these therapeutics including the ability to increase PNN degrading effectors that can downregulate PV activity. Consistent with this, we observe shared effects of these drugs in terms of their ability to significantly reduce PV levels. These findings highlight the possibility that ECM remodeling and associated hippocampal PC disinhibition represent a shared feature of varied antidepressant medications.

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Hummel, K., Shautidze, G., Thorland, E., Amontree, M., Wonnenberg, P., Blanco, I., Conant, K.. 2025-12-13. Varied monoamine reuptake inhibitors reduce parvalbumin expression; implications for pyramidal cell disinhibition and enhanced neuroplasticity. https://doi.org/10.64898/2025.12.12.693967

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