Sexual Dimorphism in Stress‐induced Hyperthermia in SNAP25Δ3 mice, a mouse model with disabled Gβγ regulation of the exocytotic fusion apparatus

• Published in: The European journal of neuroscience Vol. 52; no. 1; pp. 2815 - 2826
• Main Authors: Thompson Gray, Analisa D., Simonetti, Justice, Adegboye, Feyisayo, Jones, Carrie K., Zurawski, Zack, Hamm, Heidi E.
• Format: Journal Article
• Language: English
• Published: France Wiley Subscription Services, Inc 01.07.2020
• Subjects: Body temperature; Exocytosis; Genotypes; Gβγ; G‐protein coupled receptors; Heterozygosity; Homozygotes; Hyperthermia; Information processing; Inhibition; Mutation; nociception; Pain perception; Phenotypes; Presynapse; sex differences; Sexual dimorphism; SNAP receptors; Spatial memory; stress‐induced hyperthermia; Thermoregulation; Gβγ; nociception; stress-induced hyperthermia; G-protein coupled receptors; sex differences
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14836

Behavioral assays in the mouse can show marked differences between male and female animals of a given genotype. These differences identified in such preclinical studies may have important clinical implications. We recently made a mouse model with impaired presynaptic inhibition through Gβγ‐SNARE signaling. Here, we examine the role of sexual dimorphism in the severity of the phenotypes of this model, the SNAP25Δ3 mouse. In males, we already reported that SNAP25Δ3 homozygotes demonstrated phenotypes in motor coordination, nociception, spatial memory and stress processing. We now report that while minimal sexually dimorphic effects were observed for the nociceptive, motor or memory phenotypes, large differences were observed in the stress‐induced hyperthermia paradigm, with male SNAP25Δ3 homozygotes exhibiting an increase in body temperature subsequent to handling relative to wild‐type littermates, while no such genotype‐dependent effect was observed in females. This suggests sexually dimorphic mechanisms of Gβγ‐SNARE signaling for stress processing or thermoregulation within the mouse. Second, we examined the effects of heterozygosity with respect to the SNAP25Δ3 mutation. Heterozygote SNAP25Δ3 animals were tested alongside homozygote and wild‐type littermates in all of the aforementioned paradigms and displayed phenotypes similar to wild‐type animals or an intermediate state. From this, we conclude that the SNAP25Δ3 mutation does not behave in an autosomal dominant manner, but rather displays incomplete dominance for many phenotypes. The Gβγ‐SNARE pathway is a significant regulatory mechanism for inhibition of exocytosis Gi/o‐coupled GPCRs in a diverse variety of cell types. In this pathway, Gβγ subunits that are released by inhibitory Gi/o‐coupled GPCRs inhibit exocytosis by binding to SNAP25 located within formed SNARE complexes and displacing synaptotagmin I.