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

Abstract

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.

Gunn rats with glial activation in the hippocampus show prolonged immobility time in the forced swimming test and tail suspension test

“…The results of this study indicating that both microglia and astrocytes are significantly activated in the hippocampus of Gunn rats as shown by immunohistochemistry using Iba1 and S100B are consistent with our previous studies which demonstrated increased immunoreactivity for another microglial marker CD11b (Furuya et al., 2013; Liaury et al., 2012, 2014) and for another astrocytic marker GFAP (Limoa et al., 2016) in the hippocampal DG, CA1, and CA3. These observations of the increased immunoreactivity using two distinct markers for each glial cell substantiate both microglial activation and astrocytic activation in the hippocampus of Gunn rats.…”

“…Therefore, Gunn rats have been used as an experimental model of kernicterus (bilirubin encephalopathy), which can be considered as an organic brain disorder. As patients with organic brain disorder often present symptoms of schizophrenia and affective disorder (Hamilton, Frick, Takahashi, & Hopping, 1983), it is not unexpected that Gunn rats show depression‐like behavior as demonstrated by this study and schizophrenia‐like behavior as shown by our previous studies (Furuya et al., 2013; Liaury et al., 2012, 2014; Limoa et al., 2016). It has been shown that a neuronal damage in the hippocampus is caused by unconjugated bilirubin in growing Gunn rats (Ohno, 1981).…”

“…However, the numbers of established models which show signs or symptoms relevant to the diseases are limited. We previously demonstrated that Gunn rats with hyperbilirubinemia showed the activation of both microglia stained with CD11b (Furuya et al., 2013; Liaury et al., 2012, 2014; Limoa et al., 2016) and astrocytes stained with glial fibrillar acidic protein (GFAP) (Limoa et al., 2016) in the hippocampus and exhibited schizophrenia‐like behavior in the prepulse inhibition test (Liaury et al., 2014; Limoa et al., 2016), the object‐location test (Furuya et al., 2013), and the novel object recognition test (Liaury et al., 2014). …”

Repetitive Mild Traumatic Brain Injury in the Developing Brain: Effects on Long-Term Functional Outcome and Neuropathology

“…Iba-1 positive cells were counted as previously described 26 . To estimate the number of Iba-1 labeled microglia, images were taken using a light microscope (Nikon Eclipse 90i).…”

“…Collectively, disrupted axonal transport, ionic imbalance, and mitochondrial dysfunction can lead to axonal swelling 8,[22][23][24][25][26] , plasma membrane disruption, and release of intracellular contents, including mitochondria. The latter can act as damage associated molecular patterns and lead to recruitment or activation of inflammatory cells 48 .…”