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Mechanistic study of SENP2-PCYT1A axis regulating synaptic pruning that results in anxiety-like behavior

ABSTRACT: Anxiety disorder, one of the most common mental illnesses, is emerging as a significant public health challenge. Glial regulation of neuronal synaptic pruning offers a novel therapeutic avenue for anxiety; however, it remains unclear whether SUMO modification is involved in this regulatory process. In this study, we demonstrate that both global and microglia-specific SENP2 knockout mice exhibit anxiety-like behaviors coupled with aberrant synaptic pruning, whereas neuronal-specific knockout animals do not show these phenotypes. Moreover, SENP2 specifically modulates LC3-associated phagocytosis (LAP) in microglia and removes SUMO modifications from the target protein PCYT1A. We propose that the SENP2–PCYT1A signaling axis in microglia/astrocyte governs LAP pathway activity, thereby maintaining synaptic pruning homeostasis and preventing the onset of anxiety-like behaviors. Accordingly, this project will (1) define the precise role of LAP in microglial/astrocyte synaptic pruning, (2) elucidate the molecular mechanism by which SUMOylation regulates key factors in the LAP pathway, and (3) investigate how the SENP2–PCYT1A axis modulates synaptic stability and anxiety-related behaviors. These findings not only advance our understanding of SUMO modification in microglia–neuron immune crosstalk but also provide novel insights into potential targeted interventions and precision therapies for anxiety-related mental disorders.

ORGANISM(S): Mus Musculus

SUBMITTER: Yitao Qi

PROVIDER: PXD080104 | iProX | Tue Jun 23 00:00:00 BST 2026

REPOSITORIES: iProX

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Project description:Background Chronic anxiety imposes a major global health burden, yet existing treatments remain inadequate, with limited efficacy or significant side effects. Mitochondrial abnormalities have emerged as key contributors to anxiety-related phenotypes, suggesting that targeting mitochondrial function may offer a novel therapeutic avenue. Urolithin A (UA), a gut microbiota-derived metabolite known to enhance mitochondrial function, has shown neuroprotective effects in preclinical models of aging and neurodegeneration. However, its potential in modulating anxiety and underlying neuronal mechanisms remains unexplored. Methods We examined the effects of UA in two rodent models of heightened anxiety: a natural variation model and a genetically selected high stress-reactivity line. Animals received chronic UA supplementation, and anxiety-like behaviors were assessed across multiple paradigms. Single-nucleus RNA sequencing was performed to identify molecular alterations in nucleus accumbens (NAc) medium spiny neurons (MSNs), incorporating MitoPathway analyses to examine mitochondrion-related transcriptomic signatures. Electrophysiological, immunohistochemical, and morphological analyses were conducted to assess mitochondrial pathways and synaptic function. Results UA selectively reduced anxiety-like behaviors in high-anxiety animals, both males and females, leaving non-anxious controls unaffected. Transcriptomic analyses revealed widespread mitochondrial and synaptic dysregulation in high-anxiety MSNs, with impaired mitophagy emerging as a core feature. UA treatment restored these transcriptomic signatures, normalizing mitophagy-related pathways across all MSN subtypes tightly linked to restored synaptic pathways. These changes translated into structural and functional rescue of MSN dendritic architecture, spine density, and excitatory synaptic transmission. Conclusions These findings identify mitophagy deficits in NAc MSNs as a hallmark of heightened anxiety and highlight UA as a promising mechanism-based intervention.

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Mechanistic study of SENP2-PCYT1A axis regulating synaptic pruning that results in anxiety-like behavior

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