TY - JOUR
T1 - Sex-Specific Role for SLIT1 in Regulating Stress Susceptibility
AU - van der Zee, Yentl Y.
AU - Lardner, Casey K.
AU - Parise, Eric M.
AU - Mews, Philipp
AU - Ramakrishnan, Aarthi
AU - Patel, Vishwendra
AU - Teague, Collin D.
AU - Salery, Marine
AU - Walker, Deena M.
AU - Browne, Caleb J.
AU - Labonté, Benoit
AU - Parise, Lyonna F.
AU - Kronman, Hope
AU - Penã, Catherine J.
AU - Torres-Berrío, Angélica
AU - Duffy, Julia E.
AU - de Nijs, Laurence
AU - Eijssen, Lars M.T.
AU - Shen, Li
AU - Rutten, Bart
AU - Issler, Orna
AU - Nestler, Eric J.
N1 - Publisher Copyright:
© 2021 Society of Biological Psychiatry
PY - 2022/1/1
Y1 - 2022/1/1
N2 - Background: Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility. Methods: We discovered that SLIT1, a secreted protein essential for axonal navigation and molecular guidance during development, is downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with depression compared with healthy control subjects, but not in men with depression. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice. Results: When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex-specific increase in anxiety- and depression-related behaviors. Furthermore, we found that vmPFC Slit1 KD decreased the dendritic arborization of vmPFC pyramidal neurons and decreased the excitability of the neurons in female mice, effects not observed in males. RNA sequencing analysis of the vmPFC after Slit1 KD in female mice revealed an augmented transcriptional stress signature. Conclusions: Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the female vmPFC and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility.
AB - Background: Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility. Methods: We discovered that SLIT1, a secreted protein essential for axonal navigation and molecular guidance during development, is downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with depression compared with healthy control subjects, but not in men with depression. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice. Results: When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex-specific increase in anxiety- and depression-related behaviors. Furthermore, we found that vmPFC Slit1 KD decreased the dendritic arborization of vmPFC pyramidal neurons and decreased the excitability of the neurons in female mice, effects not observed in males. RNA sequencing analysis of the vmPFC after Slit1 KD in female mice revealed an augmented transcriptional stress signature. Conclusions: Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the female vmPFC and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility.
KW - Chronic variable stress
KW - Major depressive disorder
KW - Prefrontal cortex
KW - RNA sequencing
KW - SLIT1
UR - http://www.scopus.com/inward/record.url?scp=85106265398&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2021.01.019
DO - 10.1016/j.biopsych.2021.01.019
M3 - Article
C2 - 33896623
AN - SCOPUS:85106265398
SN - 0006-3223
VL - 91
SP - 81
EP - 91
JO - Biological Psychiatry
JF - Biological Psychiatry
IS - 1
ER -