Astrocyte‐dependent protective effect of quetiapine on GABAergic neuron is associated with the prevention of anxiety‐like behaviors in aging mice after long‐term treatment

Abstract

Previous studies have demonstrated that quetiapine (QTP) may have neuroprotective properties; however, the underlying mechanisms have not been fully elucidated. In this study, we identified a novel mechanism by which QTP increased the synthesis of ATP in astrocytes and protected GABAergic neurons from aging-induced death. In 12-month-old mice, QTP significantly improved cell number of GABAegic neurons in the cortex and ameliorated anxiety-like behaviors compared to control group. Complimentary in vitro studies showed that QTP had no direct effect on the survival of aging GABAergic neurons in culture. Astrocyte-conditioned medium (ACM) pretreated with QTP (ACM QTP ) for 24 h effectively protected GABAergic neurons against aging-induced spontaneous cell death. It was also found that QTP boosted the synthesis of ATP from cultured astrocytes after 24 h of treatment, which might be responsible for the protective effects on neurons. Consistent with the above findings, a Rhodamine 123 test showed that ACM QTP , not QTP itself, was able to prevent the decrease in mitochondrial membrane potential in the aging neurons. For the first time, our study has provided evidence that astrocytes may be the conduit through which QTP is able to exert its neuroprotective effects on GABAergic neurons.

Regulation of astrocyte pathology by fluoxetine prevents the deterioration of Alzheimer phenotypes in an APP/PS1 mouse model

“…Cerebral cortical astrocytes were prepared from 1‐day‐old APP/PS1 and wild‐type (WT) littermates as previously described (Chen et al, ; Wang et al, ), with minor modification. The astrocyte cultures were fed with Dulbecco's Modified Eagle's Medium (DMEM, Life Technologies) with 10% fetal bovine serum (FBS, Life Technologies) twice a week during the first two weeks, then the FBS‐containing DMEM was replaced with serum‐free Neurobasal media (Invitrogen; supplemented with 2% B‐27, 0.01 µg/ml basic fibroblast growth factor (bFGF) and 0.5 mM L‐glutamine).…”

“…Cerebral cortical astrocytes were prepared from 1-day-old APP/PS1 and wild-type (WT) littermates as previously described (Chen et al, 2005;Wang et al, 2014b) media (Invitrogen; supplemented with 2% B-27, 0.01 mg/ml basic fibroblast growth factor (bFGF) and 0.5 mM L-glutamine). FLX (1 mM) was added (or not) during the third and fourth weeks.…”

Heterogeneous astrocytes: Active players in CNS

“…For example, the ventral astrocytes specifically encoded Semaphorin3A (Sema3A) which is required for proper circuit organization between motor neuron and sensory neuron (Molofsky et al 2014). The heterogeneous astrocytes-mediated diverse roles in regulating brain functions is reflected not only in learning and memory but also in sleep and wakefulness (Ding et al 2013;Frank 2013;Kim et al 2014;Thrane et al 2012), behavior and emotion (Quintana et al 2013;Sandau et al 2012;Wang et al 2014;Xia et al 2013). Compared to rodents, for example, astroglial regulation of sleep in humans may be more obvious (Frank 2013).…”

Methimazole Inhibits the Expression of GFAP and the Migration of Astrocyte in Scratched Wound Model In Vitro

“…Cells and Treatments. Astrocytes were set up by using one-day-old newborn ICR mice as previously reported with minor modifications [18]. Cortical explants were isolated and cut into a 1 mm cube.…”

“…The medium was changed every 3 days. Astrocytes were used for experiments when they were 4 weeks old, which were considered as functionally mature [18]. Methimazole was purchased from Sigma and dissolved in DMEM.…”