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Brain Struct Funct. 2019 Jul;224(6):2213-2230. doi: 10.1007/s00429-019-01898-6. Epub 2019 Jun 10.

Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner.

Author information

1
Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1/A9, 48149, Munster, Germany. hohoffch@uni-muenster.de.
2
Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1/A9, 48149, Munster, Germany.
3
Department of Behavioral Biology, University of Osnabrück, Osnabrück, Germany.
4
Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience, University of Münster, Munster, Germany.
5
Cellular Neurophysiology, Center of Physiology, Hannover Medical School, Hannover, Germany.
6
Department of Clinical Radiology, University of Münster, Munster, Germany.
7
Department of Medicine, Core Facility Transgenic Animal and Genetic Engineering Models (TRAM), University of Münster, Munster, Germany.
8
Institute of Experimental Pathology, ZMBE, University of Münster, Munster, Germany.
9
Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu, 610041, China.
10
Department of Psychiatry and Psychotherapy, University of Münster, Albert-Schweitzer-Campus 1/A9, 48149, Munster, Germany. wzhang@uni-muenster.de.

Abstract

The palmitoyl acyltransferase ZDHHC7 belongs to the DHHC family responsible for the covalent attachment of palmitic acid (palmitoylation) to target proteins. Among synaptic proteins, its main targets are sex steroid receptors such as the estrogen receptors. When palmitoylated, these couple to membrane microdomains and elicit non-genomic rapid responses. Such coupling is found particularly in cortico-limbic brain areas which impact structure, function, and behavioral outcomes. Thus far, the functional role of ZDHHC7 has not been investigated in this context. To directly analyze an impact of ZDHHC7 on brain anatomy, microstructure, connectivity, function, and behavior, we generated a mutant mouse in which the Zdhhc7 gene is constitutively inactivated. Male and female Zdhhc7-/- mice were phenotypically compared with wild-type mice using behavioral tests, electrophysiology, protein analyses, and neuroimaging with diffusion tensor-based fiber tractography. Zdhhc7-deficiency impaired excitatory transmission, synaptic plasticity at hippocampal Schaffer collateral CA1 synapses, and hippocampal structural connectivity in both sexes in similar manners. Effects on both sexes but in different manners appeared in medial prefrontal cortical synaptic transmission and in hippocampal microstructures. Finally, Zdhhc7-deficiency affected anxiety-related behaviors exclusively in females. Our data demonstrated the importance of Zdhhc7 for assembling proper brain structure, function, and behavior on a system level in mice in a sex-related manner. Given the prominent role of sex-specificity also in humans and associated mental disorders, Zdhhc7-/- mice might provide a promising model for in-depth investigation of potentially underlying sex-specifically altered mechanisms.

KEYWORDS:

Behavioral phenotyping; Constitutive knockout mouse; Electrophysiological recordings; Palmitoylation; Small animal imaging; Zdhhc7-deficiency

PMID:
31183559
DOI:
10.1007/s00429-019-01898-6

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