Minocycline improves recognition memory and attenuates microglial activation in Gunn rat: A possible hyperbilirubinemia-induced 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).…”

“…It has been shown that a neuronal damage in the hippocampus is caused by unconjugated bilirubin in growing Gunn rats (Ohno, 1981). In addition, Gunn rats have been demonstrated to show impaired recognition memory (Liaury et al., 2014). Such damage of hippocampal neurons and impaired recognition memory in Gunn rats may parallel the clinical observation that depressed patients often manifest poor concentration and memory.…”

“…If this is correct, impaired behavior in Gunn rats will be ameliorated after inhibition of glial activation. Indeed, we have previously demonstrated that minocycline attenuates microglial activation in the hippocampus and improves impaired recognition memory in Gunn rats (Liaury et al., 2014). As it is becoming widely accepted that activated microglia act as immunoregulators of astrocytic activation, and vice versa (Hashioka et al., 2013; Liu, Tang, & Feng, 2011), studies of activation of microglia as well as astrocytes in the pathological brain may be very important in shedding light on the pathogenesis of psychiatric disorders.…”

“…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). …”