Deficiency of the palmitoyl acyltransferase ZDHHC7 modulates depression-like behaviour in female mice after a mild chronic stress paradigm

Abstract

Chronic stress (CS) is a debilitating condition that negatively affects body and brain. In mice, CS effects range from changes in behaviour and brain microstructure down to the level of gene expression. These effects are partly mediated by sex and sex steroid hormones, which in turn are affected by the palmitoyl acyltransferase ZDHHC7. ZDHHC7 might modulate also the response to CS via palmitoylation of sex steroid hormone receptors and other proteins critical for neuronal structure and functions. Therefore, we aimed to investigate the role of ZDHHC7 in response to CS on different system levels in a mouse model of Zdhhc7-deficiency. Female and male Zdhhc7-knockout (KO) and -wildtype (WT) mice underwent a four-week-mild CS paradigm or non-stress control (C) condition. After C or CS, behaviours, hippocampal microstructures (via MRI-based diffusion tensor imaging) and brain gene expression profiles (via mRNA-seq transcriptomics) were investigated. Analyses focused on effects of genotype (KO vs. WT) or condition (C vs. CS) separately in both sexes. Our results revealed significant effects particularly in females. Female KOs displayed increased locomotion and reduced depression-like behaviour after CS (KO vs. WT, C vs. CS: p_all < 0.05). Hippocampal fibres were reduced in female KOs after C (KO vs. WT: p_all < 0.05) but in female WTs after CS (C vs. CS: p_all < 0.05). Furthermore, female KOs showed increased cortistatin expression after CS (C vs. CS: mRNAseq and qPCR p_all < 0.05). In sum, Zdhhc7-deficiency reduced depression-like behaviours, prevented hippocampal fibre reduction and upregulated cortistatin after CS. It seemed to be related to a sex-specific stress response and may reveal genetic factors of CS-resilience in female mice.

Fig. 1. Effects of Zdhhc7-deficiency, chronic stress and sex on behaviour.

Zdhhc7 wildtype (WT) and knockout (KO) mice after control (C) or chronic stress (CS) conditions revealed differences in locomotor behavior with respect to genotype (A) or condition (B), and differences in depressive-like behaviour regarding genotype (C, E) or condition (D, F). Bars represent group means with standard error mean (±SEM) and individual data points as dots in spontaneous alternation test (SAT), social interaction test (SI) and tail suspension test (TS). Asterisks depict the level of significance (*p < 0.05; **p < 0.01; ***p < 0.001); sample sizes were n = 22–24 per group.

Fig. 2. Effects of Zdhhc7-deficiency, chronic stress and sex on brain microstructure.

Zdhhc7 wildtype (WT) and knockout (KO) mice after control (C) or chronic stress (CS) conditions revealed differences in hippocampal fibres with respect to genotype effect (A, C, E) or condition effect (B, D, F). Bars represent group means with standard error mean (±SEM) and individual data points as dots in left or right ventral hippocampus regarding fibre numbers or lengths (named in respective plots). Asterisks depict the level of significance (*p < 0.05); sample sizes were n = 4–5 per group.

Fig. 3. Effects of Zdhhc7-deficiency, chronic stress and sex on hippocampal gene expression.

Zdhhc7 wildtype (WT) and knockout (KO) mice after control (C) or chronic stress (CS) conditions revealed differences in hippocampal gene expression with respect to condition effect (A–D) or genotype effect (E–H). Bars represent group means with standard error mean (±SEM) and individual data points as dots regarding mRNA sequencing based expression (A, C, E, G) or regarding qPCR based relative expression calibrated to the control group “WT females after C” (B, D, F, H). Asterisks depict the level of significance (*p < 0.05; **p < 0.01; ***p < 0.001)); sample sizes were n = 5–6 per group.