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Interleukin-18-deficient mice develop hippocampal abnormalities related to possible depressive-like behaviors
Kyosuke Yamanishi1, Nobutaka Doe2, Keiichiro Mukai1
1Department of Neuropsychiatry, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 6638501, Japan.
Abstract:
Interleukin-18 (IL-18) is an inflammatory cytokine linked to major depressive disorder (MDD). MDD is closely related to metabolic disorders, such as diabetes mellitus (DM) and obesity. Moreover, DM is associated with cognitive impairment and promotes apoptosis of hippocampal cells by activating pro-apoptotic and inhibiting anti-apoptotic factors. IL-18-deficient (Il18-/-) mice are obese and have DM. Therefore, we hypothesized a close relationship between IL-18 and death of hippocampal cells, affecting neurogenesis related to behavioral changes such as MDD. Il18-/- male mice were generated on the C57Bl/6 background and Il18+/+ mice were used as controls. Behavioral, histopathological, and molecular responses, as well as responses to intracerebral recombinant IL-18 administration, were examined. Compared with Il18+/+ mice, Il18-/- mice had impaired learning and memory and exhibited lower motivation. In the Il18-/- mice, degenerated mitochondria were detected in synaptic terminals in the molecular layer, the polymorphic layer, and in mossy fibers in the dentate gyrus, suggesting mitochondrial abnormalities. Because of the degeneration of mitochondria in the dentate gyrus, in which pro-apoptotic molecules were upregulated and anti-apoptotic factors were decreased, apoptosis inducers were not cleaved, indicating inhibition of apoptosis. In addition, neurogenesis in the dentate gyrus and the maturity of neuronal cells were decreased in the Il18-/- mice, while intracerebral administration of recombinant IL-18 promoted significant recovery of neurogenesis. Our findings suggested that IL-18 was indispensable for mitochondrial homeostasis, sustaining clearance of degenerative neural cells, and supporting neurogenesis, normal neuronal maturation and hippocampal function.
Insights
Interleukin-18 (IL-18) deficiency impairs learning, memory, and neurogenesis by causing mitochondrial damage in hippocampal cells. Restoring IL-18 levels promotes recovery of neuronal function and hippocampal health.
Area of Science:
- Neuroscience
- Immunology
- Metabolic Disorders
Background:
- Interleukin-18 (IL-18) is an inflammatory cytokine implicated in major depressive disorder (MDD).
- MDD is linked to metabolic disorders like diabetes mellitus (DM) and obesity, which can cause cognitive impairment and hippocampal cell apoptosis.
- IL-18-deficient (Il18-/-) mice exhibit obesity and DM, suggesting a role for IL-18 in these conditions.
Purpose of the Study:
- To investigate the relationship between IL-18 and hippocampal cell death, neurogenesis, and MDD-related behaviors.
- To determine if IL-18 deficiency impacts mitochondrial function and apoptosis in the hippocampus.
- To assess the therapeutic potential of IL-18 in restoring hippocampal function.
Main Methods:
- Generation and comparison of IL-18-deficient (Il18-/-) and wild-type (Il18+/+) male mice on a C57Bl/6 background.
- Behavioral testing to assess learning, memory, and motivation.
- Histopathological and molecular analyses of hippocampal tissue, focusing on mitochondria, apoptosis, and neurogenesis.
- Examination of responses to intracerebral recombinant IL-18 administration.
Main Results:
- Il18-/- mice displayed impaired learning, memory, and reduced motivation compared to controls.
- Mitochondrial degeneration was observed in the dentate gyrus of Il18-/- mice, alongside altered expression of apoptotic factors and decreased neurogenesis.
- Intracerebral administration of recombinant IL-18 significantly improved neurogenesis and neuronal maturation in Il18-/- mice.
Conclusions:
- IL-18 is crucial for maintaining mitochondrial homeostasis in hippocampal neurons.
- IL-18 supports the clearance of degenerated neural cells and promotes neurogenesis and neuronal maturation.
- IL-18 plays a vital role in hippocampal function and may be a therapeutic target for MDD and related cognitive impairments.
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