Hippocampus-specific deficiency of IL-15Rα contributes to greater anxiety-like behaviors in mice

Nguyen, Linda; Bohlen, Joseph F.; Stricker, Janelle C.; Chahal, Ikttesh; Zhang, Hanting; Pistilli, Emidio E.

doi:10.1007/s11011-016-9930-y

Cited by 9 publications

(4 citation statements)

References 26 publications

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“…Several published reports have confirmed that IL-15Rα insufficiency results in multiple disorders, including but not limited to immunodeficiency, skeletal muscle variations, and a range of neurological symptoms (24,(50)(51)(52)(53)(54). The presence of inflammation is an essential etiological hypothesis in psychiatric diseases, including schizophrenia and depression, and we observed alterations in the serum levels of IL-15Rα in patients with schizophrenia and depression in this study.…”

Section: Discussionsupporting

confidence: 82%

Reduced Serum Levels of Soluble Interleukin-15 Receptor α in Schizophrenia and Its Relationship to the Excited Phenotype

Mao

et al. 2022

Front. Psychiatry

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Our previous studies documented that interleukin-15 receptor α (IL-15Rα) knockout (KO) mice exhibited hyperactivity, memory impairment, and desperate behavior, which are core features of schizophrenia and depression. Due to the overlapping symptomology and pathogenesis observed for schizophrenia and depression, the present study attempted to determine whether IL-15Rα was associated with the risk of schizophrenia or depression. One hundred fifty-six participants, including 63 schizophrenia patients, 29 depressive patients, and 64 age-matched healthy controls, were enrolled in the study. We investigated the circulating levels of soluble IL-15Rα and analyzed potential links between the IL-15Rα levels and clinical symptoms present in schizophrenia or depressive patients. We observed reduced serum IL-15Rα levels in schizophrenia patients, but not depressive patients compared with controls. Moreover, a significant negative association was observed between the circulating IL-15Rα levels and excited phenotypes in the schizophrenia patients. The IL-15Rα KO mice displayed pronounced pre-pulse inhibition impairment, which was a typical symptom of schizophrenia. Interestingly, the IL-15Rα KO mice exhibited a remarkable elevation in the startle amplitude in the startle reflex test compared to wild type mice. These results demonstrated that serum levels of soluble IL-15Rα were reduced in schizophrenia and highlighted the relationship of IL-15Rα and the excited phenotype in schizophrenia patients and mice.

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Section: Discussionsupporting

confidence: 82%

Reduced Serum Levels of Soluble Interleukin-15 Receptor α in Schizophrenia and Its Relationship to the Excited Phenotype

Mao

et al. 2022

Front. Psychiatry

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“…Additionally, injured female mice in this model display more anxiety-like behavior in the open field performance, and TH does not provide protection in this testing domain either. Although mice have a natural tendency to explore the periphery more than the unprotected center areas while in the open field, mice with anxiety like behavior spent even more time in the periphery than the center than did shams [80,81]. Congruent with these findings, a higher prevalence of anxiety disorders and increased impulsivity and compulsivity characterize HIE survivors [82].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Hypothermia Provides Variable Protection against Behavioral Deficits after Neonatal Hypoxia-Ischemia: A Potential Role for Brain-Derived Neurotrophic Factor

et al. 2017

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Background: Despite treatment with therapeutic hypothermia (TH), infants who survive hypoxic ischemic (HI) encephalopathy (HIE) have persistent neurological abnormalities at school age. Protection by TH against HI brain injury is variable in both humans and animal models. Our current preclinical model of hypoxia-ischemia (HI) and TH displays this variability of outcomes in neuropathological and neuroimaging end points with some sexual dimorphism. The detailed behavioral phenotype of this model is unknown. Whether there is sexual dimorphism in certain behavioral domains is also not known. Brain-derived neurotrophic factor (BDNF) supports neuronal cell survival and repair but may also be a marker of injury. Here, we characterize the behavioral deficits after HI and TH stratified by sex, as well as late changes in BDNF and its correlation with memory impairment. Methods: HI was induced in C57BL6 mice on postnatal day 10 (p10) (modified Vannucci model). Mice were randomized to TH (31°C) or normothermia (NT, 36°C) for 4 h after HI. Controls were anesthesia-exposed, age- and sex-matched littermates. Between p16 and p39, growth was followed, and behavioral testing was performed including reflexes (air righting, forelimb grasp and negative geotaxis) and sensorimotor, learning, and memory skills (open field, balance beam, adhesive removal, Y-maze tests, and object location task [OLT]). Correlations between mature BDNF levels in the forebrain and p42 memory outcomes were studied. Results: Both male and female HI mice had an approximately 8-12% lower growth rate (g/day) than shams (p ≤ 0.01) by p39. TH ameliorated this growth failure in females but not in males. In female mice, HI injury prolonged the time spent at the periphery (open field) at p36 (p = 0.004), regardless of treatment. TH prevented motor impairments in the balance beam and adhesive removal tests in male and female mice, respectively (p ≤ 0.05). Male and female HI mice visited the new arm of the Y-maze 12.5% (p = 0.05) and 10% (p = 0.03) less often than shams, respectively. Male HI mice also had 35% lower exploratory preference score than sham (p ≤ 0.001) in the OLT. TH did not prevent memory impairments found with Y-maze testing or OLT in either sex (p ≤ 0.01) at p26. At p42, BDNF levels in the forebrain ipsilateral to the HI insult were 1.7- to 2-fold higher than BDNF levels in the sham forebrain, and TH did not prevent this increase. Higher BDNF levels in the forebrain ipsilateral to the insult correlated with worse performance in the Y-maze in both sexes and in OLT in male mice (p = 0.01). Conclusions: TH provides benefit in specific domains of behavior following neonatal HI. In general, these benefits accrued to both males and females, but not in all areas. In some domains, such as memory, no benefit of TH was found. Late differences in individual BDNF levels may explain some of these findings.

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“…The cytokine/myokine IL15 and its primary binding partner IL15RA, besides their well-studied role in T and natural killer (NK) cell physiology, participate in the regulation of energy processes in a variety of other tissues (He et al, 2010), including brain (Wu et al, 2010;Nguyen et al, 2017), bone (Djaafar et al, 2010;Loro et al, 2017) and muscle (Quinn et al, 2013;Pistilli et al, 2011;Loro et al, 2015). Fast muscles of mice lacking IL15RA (Il15ra −/− ) are fatigue resistant (Pistilli et al, 2011) and their mitochondria more efficiently oxidize fatty acids as primary energy fuel (Loro et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial ultrastructural adaptations in fast muscles of mice lacking IL15RA

Loro

Bisetto

Khurana

2018

Journal of Cell Science

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The pro-inflammatory cytokine interleukin-15 (IL15) and its receptor α (IL15RA) participate in the regulation of musculoskeletal function and metabolism. Deletion of the Il15ra gene in mice increases spontaneous activity, improves fatigue resistance in the glycolytic extensor digitorum longus (EDL) and protects from diet-induced obesity. In humans, IL15RA single-nucleotide polymorphisms (SNPs) have been linked to muscle strength, metabolism and performance in elite endurance athletes. Taken together, these features suggest a possible role for IL15RA in muscle mitochondrial structure and function. Here, we have investigated the consequences of loss of IL15RA on skeletal muscle fiber-type properties and mitochondrial ultrastructure. Immunostaining of the EDL for myosin heavy chain (MyHC) isoforms revealed no significant changes in fiber type. Electron microscopy (EM) analysis of the EDL indicated an overall higher mitochondria content, and increased cristae density in subsarcolemmal and A-band mitochondrial subpopulations. The higher cristae density in Il15ra −/− mitochondria was associated with higher OPA1 and cardiolipin levels. Overall, these data extend our understanding of the role of IL15RA signaling in muscle oxidative metabolism and adaptation to exercise.

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Hippocampus-specific deficiency of IL-15Rα contributes to greater anxiety-like behaviors in mice

Cited by 9 publications

References 26 publications

Reduced Serum Levels of Soluble Interleukin-15 Receptor α in Schizophrenia and Its Relationship to the Excited Phenotype

Reduced Serum Levels of Soluble Interleukin-15 Receptor α in Schizophrenia and Its Relationship to the Excited Phenotype

Therapeutic Hypothermia Provides Variable Protection against Behavioral Deficits after Neonatal Hypoxia-Ischemia: A Potential Role for Brain-Derived Neurotrophic Factor

Mitochondrial ultrastructural adaptations in fast muscles of mice lacking IL15RA

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