Abstract
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.
Highlights
Chronic stress strongly contributes to the manifestation of many diseases including neurological, neurodegenerative, and psychiatric disorders, such as anxiety and depression [1,2,3,4]
Immuno-electron microscopy (IEM) further confirmed that p11 cell polarity and cerebrospinal fluid (CSF) flow To investigate the molecular mechanisms by which p11 regulates was selectively enriched in the ependymal cell layer (EL), but not in the ventricular lumen (VL) and brain parenchyma (BP) (Fig. 1b)
Our previous studies have shown that p11 is a key causal factor for depression, and mediates stress responses and antidepressant actions in mice and humans [8]. p11 is present in various neuronal circuits in distinct neuronal types, such as cholinergic neurons in nucleus accumbens [28], mossy cells and basket cells in dentate gyrus [9], and layer 5 corticostriatal projection neurons [38], involved in emotional control
Summary
Chronic stress strongly contributes to the manifestation of many diseases including neurological, neurodegenerative, and psychiatric disorders, such as anxiety and depression [1,2,3,4]. Ependymal cells are polarized in the epithelial plane and orient their motile cilia, which is determined by the basal body and basal foot orientation, in a common direction to efficiently propel the cerebrospinal fluid (CSF) [13, 14]. Neurodegenerative, and psychiatric disorders in humans have been associated with abnormal CSF flow [22,23,24,25,26]. We show that ependymal p11 is critically important for PCP, CSF flow, and depression
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