Characterization of an epigenetic model of depression linked to neuroinflammation and impaired neuroplasticity

Background

Major depression (MD) is a prevalent neuropsychiatric disorder associated with persistent mood and cognitive disturbances, linked to dysregulation of epigenetic, neurotrophic, and neuroimmune mechanisms in brain regions critical for emotional regulation. Histone deacetylase 5 (HDAC5) is a key epigenetic regulator in the medial prefrontal cortex (mPFC) and hippocampus, areas implicated in mood disorders [1]. Elevated HDAC5 expression has been observed in peripheral immune cells of patients with MD and in post-mortem prefrontal cortex samples, correlating with reduced brain-derived neurotrophic factor (BDNF) expression and increased neuroinflammatory responses [2]. However, the impact of HDAC5 activity and associated histone modifications on these processes remains poorly understood

Objectives

This study aimed to investigate the behavioural and molecular effects of HDAC5 overexpression in the mPFC of adult mice. By selectively overexpressing HDAC5 and a constitutively nuclear form (HDAC5-3SA), we examined its role in depressive and anxiety-like behaviours, neuroplasticity and neuroinflammatory processes. In addition, we aim to explore brain–immune system interactions by analyzing in these animal models the peripheral inflammatory immune response.

Methods

Using adeno-associated viral vectors (AAVs), HDAC5 or nuclear HDAC5 (HDAC5-3SA) were overexpressed in the mPFC of male and female mice, and compared to a green fluorescent protein (GFP) PFC overexpression as control group. Three weeks after AAV injection a battery of behavioral test was applied including sucrose intake test, social interaction, marble burying, elevated plus maze and open field. On week 6, animals were sacrificed and the mPFC dissected. Neuroplasticity and neuroinflammatory markers such as Bdnf, Iba1, Il6,and Tnfα mRNA levels were quantified by qPCR (n=10 mice/group). Class II HDAC enzymatic activity and histone H3 acetylation levels were also measured. Additional animals (n=6/group/sex) were perfused, and brains processed for immunohistochemistry to evaluate HDAC5, IBA1 and CD68 expression by optical density. Data were analyzed using one- and two-way ANOVA or Kruskal–Wallis tests with Tukey post-hoc; significance was set at p < 0.05

Results

HDAC5-3SA overexpression induced a depressive-like phenotype with increased anhedonia, anxiety-like behaviors and hyperlocomotion. Bdnf expression was reduced only in females (p<0.05), indicating sex-dependent transcriptional repression. Class II HDAC enzymatic activity was increased in both WT and mutant groups compared to controls. Moreover, mice overexpressing HDAC5-3SA in the PFC showed a marked increase in IBA1 and CD68 immunoreactivity (p<0.05) together with increasedIl6 (p<0.05) and Tnfα (p<0.01) mRNA expression in the PFC, consistent with microglial activation and a proinflammatory neuroimmune response. Further, altered inflammatory response was detected in circulating peripheral immune cells.

Conclusion: HDAC5 overexpression in the mPFC induces depressive-like behaviour associated with epigenetic dysregulation, enhanced neuroinflammation and impaired neuroplasticity. These effects are more pronounced when HDAC5 overexpression is restricted to the nuclear compartment. Moreover, there are sex-dependent differences in vulnerability to depressive phenotype. Ongoing work is exploring whether antidepressant drug intervention can modulate the observed altered behavioral and molecular phenotype.

References

Cortés-Erice, M., Garayo-Larrea, A., Fernández-Ovejero, R. et al. Epigenetic, neuroplasticity, and adrenergic targets associated with major depression in immune cells. Sci Rep 16, 12318 (2026). https://doi.org/10.1038/s41598-026-36954-9
Tsankova, N. M., Berton, O., Renthal, W., Kumar, A., Neve, R. L., & Nestler, E. J. (2006). Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressantaction.NatureNeuroscience,9(4),519–525.https://doi.org/10.1038/nn1659