Yentl Y van der Zee1, Casey K Lardner2, Eric M Parise2, Philipp Mews2, Aarthi Ramakrishnan2, Vishwendra Patel2, Collin D Teague2, Marine Salery2, Deena M Walker2, Caleb J Browne2, Benoit Labonté2, Lyonna F Parise2, Hope Kronman2, Catherine J Penã2, Angélica Torres-Berrío2, Julia E Duffy2, Laurence de Nijs3, Lars M T Eijssen3, Li Shen2, Bart Rutten3, Orna Issler4, Eric J Nestler5. 1. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 2. Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 3. Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. 4. Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: orna.issler@mssm.edu. 5. Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: eric.nestler@mssm.edu.
Abstract
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.
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.
Authors: Marianne L Seney; Zhiguang Huo; Kelly Cahill; Leon French; Rachel Puralewski; Joyce Zhang; Ryan W Logan; George Tseng; David A Lewis; Etienne Sibille Journal: Biol Psychiatry Date: 2018-02-19 Impact factor: 13.382
Authors: Benoit Labonté; Olivia Engmann; Immanuel Purushothaman; Caroline Menard; Junshi Wang; Chunfeng Tan; Joseph R Scarpa; Gregory Moy; Yong-Hwee E Loh; Michael Cahill; Zachary S Lorsch; Peter J Hamilton; Erin S Calipari; Georgia E Hodes; Orna Issler; Hope Kronman; Madeline Pfau; Aleksandar L J Obradovic; Yan Dong; Rachael L Neve; Scott Russo; Andrew Kazarskis; Carol Tamminga; Naguib Mechawar; Gustavo Turecki; Bin Zhang; Li Shen; Eric J Nestler Journal: Nat Med Date: 2017-08-21 Impact factor: 53.440