Genetic deletion of NAPE-PLD alters stress responsiveness and HPA-axis functionality in a context-dependent manner in mice

Woodward, Taylor J. and Dimen, Diana and Sizemore, Emily Fender and Stockman, Sarah and Kazi, Fezaan and Luquet, Serge and Mackie, Ken and Katona, István and Hohmann, Andrea G. (2025) Genetic deletion of NAPE-PLD alters stress responsiveness and HPA-axis functionality in a context-dependent manner in mice. NEUROPHARMACOLOGY, 281. No.-110702. ISSN 0028-3908

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Abstract

The endocannabinoid (eCB) system regulates stress responsiveness and hypothalamic-pituitary-adrenal (HPA) axis activity. The enzyme N-acyl phosphatidylethanolamine phospholipase-D (NAPE-PLD) is primarily responsible for the synthesis of the endocannabinoid signaling molecule anandamide (AEA) and other structurally related lipid signaling molecules known as N-acylethanolamines (NAEs). However, little is known about how activity of this enzyme affects behavior. As AEA plays a regulatory role in stress adaptation, we hypothesized that reducing synthesis of AEA and other NAEs would dysregulate stress reactivity. To test this hypothesis, we evaluated wild type (WT) and NAPE-PLD knockout (KO) mice in behavioral assays that assess stress responsiveness and anxiety-like behavior. NAPE-PLD KO mice exhibited anxiety-like behaviors in the open field test after a period of single housing. NAPE-PLD KO mice exhibited an exaggerated freezing response at baseline but blunted response 2,3,5-trimethyl-3-thiazoline (TMT) predator odor when compared to WT mice. NAPE-PLD KO mice also exhibited a context-dependent dysregulation of HPA axis in response to TMT in the paraventricular hypothalamic nucleus at a neuronal level, as measured by c-Fos immunohistochemstry. Male, but not female, NAPE-PLD knockout mice showed higher levels of circulating corticosterone relative to same-sex wildtype mice in response to TMT exposure, suggesting a sexually dimorphic dysregulation of the HPA axis at the hormonal level. Sex specific findings observed here mirror the sexually dimorphic drug response we recently identified in NAPE-PLD KO mice (Woodward et al., 2025). Together, these findings suggest that the enzymatic activity of NAPE-PLD regulates emotional resilience and recovery from both acute and sustained stress.

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