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Title: | Preclinical and clinical evidence for IL-6 and CCL2 as potential mediators in the pathophysiology of psychosis | Authors: | TRIPPAERS, Chloe Lee, B. J. Hayes, L. Fukudome, D. Namkung, H. Srivastava, R. Kung, J. Morimura, K. Kato, M. Jaaro-Peled, H. Kano, S. Kirkwood, A. Yang, K. Ishizuka, K. BRONE, Bert Saito, A. Sawa, A. |
Issue Date: | 2023 | Publisher: | WILEY | Source: | GLIA, 71 , p. E1059 | Abstract: | Immune dysregulation in the brain may contribute to the pathophysiology of psychosis in disorders such as schizophrenia. Our studies of cerebrospinal fluid from patients with first episode psychosis (FEP) have shown elevation of IL-6 as well as another cytokine, CCL2. In parallel, our preclinical studies have identified a novel animal model elicited by cuprizone short-term exposure (CSE), which features upregulation of IL-6 and CCL2 (instead of demyelination, in contrast to long-term exposure to cuprizone), as well as augmented locomotor response to psychostimulants such as amphetamine. Since this behavioral phenotype is highly analogous to the psychostimulant hypersensitivity observed in human patients with psychosis, it may play an important role in the pathophysiological basis of psychosis. Our investigation shows that the CSE behavioral phenotype is ameliorated by the knockdown of IL-6 in astrocytes and CCR2 (the cognate receptor of CCL2) in CaMKII neurons of the dorsal hippocampus (dHPC). We also found hyperexcitability in dHPC CA1 pyramidal neurons which propagates through the ventral hippocampus and causes increased neuronal activity in the medial striatum. Our data thus indicate that IL-6, CCL2, and CCR2 mediate a signaling interaction from astrocytes to neurons, leading to neuronal hyperexcitability in the dHPC, and that this is sufficient to induce amphetamine hypersensitivity. These findings may elucidate how IL-6 can contribute to the pathophysiology of psychosis. | Document URI: | http://hdl.handle.net/1942/42856 | ISSN: | 0894-1491 | e-ISSN: | 1098-1136 | ISI #: | 001191372500892 | Category: | M | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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