Hyperbilirubinemia-related behavioral and neuropathological changes in rats: A possible schizophrenia animal model

Hayashida, Maiko; Miyaoka, Tsuyoshi; Tsuchie, Keiko; Yasuda, Hideaki; Wake, Rei; Nishida, Akira; Inagaki, Takuji; Toga, Tomoko; Nagami, Haruhiko; Oda, Teiji; Horiguchi, Jun

doi:10.1016/j.pnpbp.2009.02.013

Cited by 32 publications

(25 citation statements)

References 36 publications

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“…Moreover, numerous studies have confirmed the PPI deficiency in schizophrenic patients [46–48] and that antipsychotic drugs can not only ameliorate symptoms of schizophrenia but also improve the PPI deficit [49, 50]. Our previous studies have demonstrated that Gunn rats exhibit a schizophrenia-like behavior which consists of impaired sensorimotor gating as shown by decreased %PPI compared to Wistar rats, a normal rat strain [25, 26, 28]. Accordingly, Gunn rats showing such a schizophrenia-like behavior seems to be an appropriate animal model to investigate the therapeutic mechanism of ECS, the animal counterpart of ECT.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study has indicated that Gunn rats show the increased number of apoptotic cells and reduced neurogenesis in the subgranular zone of their hippocampi [25]. Zarubenko et al [75] have shown that repeated ECS causes neuronal death.…”

Section: Discussionmentioning

confidence: 99%

“…A startle response measurement system (SR-Lab, San Diego Instruments, Inc., CA) was used as described previously [25, 28]. Each animal ( n = 8 for each group) was placed in a plexiglass cylinder where it was exposed to white background noise at 65 dB for a 5-min acclimatization period.…”

Section: Methodsmentioning

confidence: 99%

“…This deficiency leads to high levels of unconjugated bilirubin in their blood and various tissue, including the brain [23, 24]. Our previous studies have revealed that Gunn rats show a behavioral abnormality similar to schizophrenia with deficits in prepulse inhibition (PPI) [25, 26]. Furthermore, we have shown that microglia are activated in the hippocampal dentate gyrus (DG) of Gunn rats [27, 28].…”

Section: Introductionmentioning

confidence: 99%

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Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat

Limoa

Hashioka

Miyaoka

et al. 2016

J Neuroinflammation

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BackgroundAlthough electroconvulsive therapy (ECT) is regarded as one of the efficient treatments for intractable psychiatric disorders, the mechanism of therapeutic action remains unclear. Recently, many studies indicate that ECT affects the immune-related cells, such as microglia, astrocytes, and lymphocytes. Moreover, microglial activation and astrocytic activation have been implicated in the postmortem brains of schizophrenia patients. We previously demonstrated that Gunn rats showed schizophrenia-like behavior and microglial activation in their brains. The present study examined the effects of electroconvulsive shock (ECS), an animal counterpart of ECT, on schizophrenia-like behavior, microgliosis, and astrogliosis in the brain of Gunn rats.MethodsThe rats were divided into four groups, i.e., Wistar sham, Wistar ECS, Gunn sham, and Gunn ECS. ECS groups received ECS once daily for six consecutive days. Subsequently, prepulse inhibition (PPI) test was performed, and immunohistochemistry analysis was carried out to determine the activation degree of microglia and astrocytes in the hippocampus by using anti-CD11b and anti-glial fibrillary acidic protein (GFAP) antibody, respectively.ResultsWe found PPI deficit in Gunn rats compared to Wistar rats, and it was significantly improved by ECS. Immunohistochemistry analysis revealed that immunoreactivity of CD11b and GFAP was significantly increased in Gunn rats compared to Wistar rats. ECS significantly attenuated the immunoreactivity of both CD11b and GFAP in Gunn rats.ConclusionsECS ameliorated schizophrenia-like behavior of Gunn rats and attenuated microgliosis and astrogliosis in the hippocampus of Gunn rats. Accordingly, therapeutic effects of ECT may be exerted, at least in part, by inhibition of glial activation. These results may provide crucial information to elucidate the role of activated glia in the pathogenesis of schizophrenia and to determine whether future therapeutic interventions should attempt to up-regulate or down-regulate glial functions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0688-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat

Limoa

Hashioka

Miyaoka

et al. 2016

J Neuroinflammation

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“…Our previous study showed behavioral abnormalities, deficits in prepulse inhibition (PPI), and neuropathological changes in Gunn rats that are similar to the characteristics of schizophrenia [22]. The Gunn rat, a mutant of the Wistar strain [23], has a genetic deficiency in glucuronyl transferase and has been used as an animal model of bilirubin encephalopathy.…”

Section: Introductionmentioning

confidence: 99%

Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model

Liaury

Miyaoka

Tsumori

et al. 2012

J Neuroinflammation

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Background: Schizophrenia is a debilitating and complex mental disorder whose exact etiology remains unknown. There is growing amount of evidence of a relationship between neuroinflammation, as demonstrated by microglial activation, and schizophrenia. Our previous studies have proposed that hyperbilirubinemia plays a role in the pathophysiology of schizophrenia. Furthermore, we suggested the Gunn rat, an animal model of bilirubin encephalopathy, as a possible animal model of schizophrenia. However, the effects of unconjugated bilirubin on microglia, the resident immune cell of the CNS, in Gunn rats have never been investigated. In the present study, we examined how microglial cells respond to bilirubin toxicity in adult Gunn rats. Methods: Using immunohistochemical techniques, we compared the distribution, morphology, and ultrastructural features of microglial cells in Gunn rats with Wistar rats as a normal control. We also determined the ratio of activated and resting microglia and observed microglia-neuron interactions. We characterized the microglial cells in the hippocampal dentate gyrus. Results: We found that microglial cells showed activated morphology in the hilus, subgranular zone, and granular layer of the Gunn rat hippocampal dentate gyrus. There was no significant difference between cell numbers between in Gunn rats and controls. However, there was significant difference in the area of CD11b expression in the hippocampal dentate gyrus. Ultrastructurally, microglial cells often contained rich enlarged rich organelles in the cytoplasm and showed some phagocytic function. Conclusions: We propose that activation of microglia could be an important causal factor of the behavioral abnormalities and neuropathological changes in Gunn rats. These findings may provide basic information for further assessment of the Gunn rat as an animal model of schizophrenia.

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Ribosomal DNA transcription in the dorsal raphe nucleus is increased in residual but not in paranoid schizophrenia

Krzyżanowska

Steiner

Brisch

et al. 2014

Eur Arch Psychiatry Clin Neurosci

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The central serotonergic system is implicated in the pathogenesis of schizophrenia, where the imbalance between dopamine, serotonin and glutamate plays a key pathophysiological role. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in schizophrenia patients. The study was carried out on paraffin-embedded brains from 17 (8 paranoid and 9 residual) schizophrenia patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver-staining method. An increased rDNA transcriptional activity was found in schizophrenia patients in the cumulative analysis of all DRN subnuclei (t test, P = 0.02). Further subgroup analysis revealed that it was an effect specific for residual schizophrenia versus paranoid schizophrenia or control groups (ANOVA, P = 0.002). This effect was confounded neither by suicide nor by antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in schizophrenia, particularly in residual patients. An activation of the rDNA transcription in DRN neurons may represent a compensatory mechanism to overcome the previously described prefrontal serotonergic hypofunction in this diagnostic subgroup.

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Hyperbilirubinemia-related behavioral and neuropathological changes in rats: A possible schizophrenia animal model

Cited by 32 publications

References 36 publications

Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat

Electroconvulsive shock attenuated microgliosis and astrogliosis in the hippocampus and ameliorated schizophrenia-like behavior of Gunn rat

Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model

Ribosomal DNA transcription in the dorsal raphe nucleus is increased in residual but not in paranoid schizophrenia

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