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

Abstract

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.

Gβγ-SNAP25 exocytotic brake removal enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity

“…We assessed whether disabling the Gβγ-SNARE interaction alters the response to physiologic stressors, since we had previously reported that Snap25 Δ3/Δ3 mice had an altered behavioral response to acute physiological stressors, specifically elevated stress-induced hyperthermia ( 16 , 25 ). We performed calorimetric studies in which energy expenditure and feeding behavior in chow-fed Snap25 +/+ and Snap25 Δ3/Δ3 mice were measured at a standard housing temperature (22°C).…”

“…The mice were then exposed to an acute cold challenge (6°C) to assess whether they could mount a physiologic response by increasing energy expenditure and food intake. assessed whether disabling the Gβγ-SNARE interaction alters the response to physiologic stressors, since we had previously reported that Snap25 Δ3/Δ3 mice had an altered behavioral response to acute physiological stressors, specifically elevated stressinduced hyperthermia (16,25). We performed calorimetric stud- Protection from HFD-induced obesity and adiposity in Snap25 Δ3/Δ3 mice.…”

“…We sought to come up with a way to effectively “turn off” the actions of the SNAP25Δ3 mutation. Our prior work shows that Snap25 Δ3/Δ3 mice have an exacerbated response to stress ( 16 , 25 ). It is known that room temperature housing is a mild cold stress for mice ( 57 , 58 ) and that cold stress can induce WAT beiging ( 59 ).…”

Polymorphism of Estrogen Receptor Genes and Its Interactions With Neurodevelopmental Genes in Attention Deficit Hyperactivity Disorder Among Chinese Han Descent

“…Feng et al [ 26 ] reported that SNAP25 rs362987 polymorphisms significantly increase ADHD risk. Sex differences in altered stress responses were reported in SNAP25 mutant mice [ 27 ]. Similarly, some CDH13 SNPs, which negative regulator of axon growth during neural differentiation, were revealed to contribute ADHD pathophysiology, particularly rs6565113 [ 28 ].…”

G protein βγ subunits bind to and inhibit the function of multiple Qa- and Qb,c-SNARE isoforms

“…The consequences of chronic, global disruption of the Gβγ-SNARE interaction have been studied in the mouse as a model system. Mutagenesis of SNAP25 to a mutant SNAP25Δ3 that interacts less well with Gβγ leads to physiological consequences, including deficits in stress processing and depressive phenotypes 16,22 .…”