TY - JOUR
T1 - Ependymal cells-CSF flow regulates stress-induced depression
AU - Seo, Ji Seon
AU - Mantas, Ioannis
AU - Svenningsson, Per
AU - Greengard, Paul
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Major depressive disorder (MDD) is a severe, common mood disorder. While reduced cerebrospinal fluid (CSF) flow adversely affects brain metabolism and fluid balance in the aging population and during development, only indirect evidence links aberrant CSF circulation with many diseases including neurological, neurodegenerative, and psychiatric disorders, such as anxiety and depression. Here we show a very high concentration of p11 as a key molecular determinant for depression in ependymal cells, which is significantly decreased in patients with MDD, and in two mouse models of depression induced by chronic stress, such as restraint and social isolation. The loss of p11 in ependymal cells causes disoriented ependymal planar cell polarity (PCP), reduced CSF flow, and depression-like and anxiety-like behaviors. p11 intrinsically controls PCP core genes, which mediates CSF flow. Viral expression of p11 in ependymal cells specifically rescues the pathophysiological and behavioral deficits caused by loss of p11. Taken together, our results identify a new role and a key molecular determinant for ependymal cell-driven CSF flow in mood disorders and suggest a novel strategy for development of treatments for stress-associated neurological, neurodegenerative, and psychiatric disorders.
AB - Major depressive disorder (MDD) is a severe, common mood disorder. While reduced cerebrospinal fluid (CSF) flow adversely affects brain metabolism and fluid balance in the aging population and during development, only indirect evidence links aberrant CSF circulation with many diseases including neurological, neurodegenerative, and psychiatric disorders, such as anxiety and depression. Here we show a very high concentration of p11 as a key molecular determinant for depression in ependymal cells, which is significantly decreased in patients with MDD, and in two mouse models of depression induced by chronic stress, such as restraint and social isolation. The loss of p11 in ependymal cells causes disoriented ependymal planar cell polarity (PCP), reduced CSF flow, and depression-like and anxiety-like behaviors. p11 intrinsically controls PCP core genes, which mediates CSF flow. Viral expression of p11 in ependymal cells specifically rescues the pathophysiological and behavioral deficits caused by loss of p11. Taken together, our results identify a new role and a key molecular determinant for ependymal cell-driven CSF flow in mood disorders and suggest a novel strategy for development of treatments for stress-associated neurological, neurodegenerative, and psychiatric disorders.
UR - http://www.scopus.com/inward/record.url?scp=85109839978&partnerID=8YFLogxK
U2 - 10.1038/s41380-021-01202-1
DO - 10.1038/s41380-021-01202-1
M3 - Article
C2 - 34234280
AN - SCOPUS:85109839978
SN - 1359-4184
VL - 26
SP - 7308
EP - 7315
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 12
ER -