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Acute stress reveals different impacts in male and female Zdhhc7-deficient mice
Nicole Kerkenberg1,2, Christa Hohoff3, Mingyue Zhang3
1Department of Mental Health, University of Münster, Münster, Germany. Nicole.Kerkenberg@ukmuenster.de.
Insights
The palmitoyl acyltransferase ZDHHC7 influences brain development and stress responses. ZDHHC7 deficiency causes sex-specific alterations in synaptic plasticity and stress resilience, potentially via estrogen receptor pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The enzyme ZDHHC7 palmitoylates key synaptic proteins and hormone receptors, impacting neuronal development and plasticity.
- ZDHHC7's role in palmitoylating sex steroid hormone receptors suggests a link to stress-related mental disorders.
Purpose of the Study:
- To investigate the role of ZDHHC7 in modulating stress responses in mice.
- To examine the sex-specific effects of ZDHHC7 deficiency on behavior, brain microstructure, gene expression, and synaptic plasticity under acute stress.
Main Methods:
- Utilized ZDHHC7 gene knockout (KO) and wild-type (WT) mice of both sexes, exposed to acute stressors.
- Assessed behavioral responses, brain microstructure (hippocampal fiber length), gene expression (Estrogen Receptors), and synaptic plasticity.
Main Results:
- Acute stress reduced estrogen receptor mRNA in male WT and KO mice.
- Male KO mice exhibited reduced hippocampal fiber length after acute stress.
- ZDHHC7 deficiency impaired synaptic plasticity in both sexes; acute stress improved it in females but not males.
Conclusions:
- ZDHHC7 plays a significant modulatory role in the brain, influencing sex-specific stress responses.
- Estrogen receptor-mediated signaling pathways are likely involved in ZDHHC7's effects on stress resilience.
- Findings highlight ZDHHC7 as a potential target for understanding and treating stress-related neurological conditions.
Abstract:
Numerous processes of neuronal development and synaptic plasticity in the brain rely on the palmitoyl acyltransferase ZDHHC7, as it palmitoylates various synaptic and extrasynaptic proteins such as neural cell adhesion molecule (NCAM) or gamma-aminobutyric acid (GABAA) receptors. In addition, ZDHHC7 palmitoylates sex steroid hormone receptors and is, therefore, indirectly linked to mental disorders that often occur because of or in conjunction with stress. In this work, we investigated how ZDHHC7 affects stress responses in mice. For this purpose, genetically modified mice with a knockout of the Zdhhc7 gene (KO) and wild-type (WT) littermates of both sexes were exposed to acute stressors or control conditions and examined with regard to their behavior, brain microstructure, gene expression, and synaptic plasticity. While no behavioral effects of acute stress were found, we did find that acute stress caused reduced mRNA levels of Esr1 and Esr2 coding for estrogen receptor α and β in the medial prefrontal cortex of male WT and KO mice. Strikingly, after acute stress only male KO mice showed reduced mean fiber lengths of the medioventral hippocampus. Furthermore, Zdhhc7-deficiency impaired synaptic plasticity in mice of both sexes, while acute stress improved it in females, but not in male mice. Taken together, our findings suggest that ZDHHC7 plays a modulatory role in the brain that leads to sex-specific stress responses, possibly due to estrogen receptor-mediated signaling pathways.
