Shu-Ji Li

Astrocyte-derived ATP modulates depressive-like behaviors

Major depressive disorder (MDD) is a cause of disability that affects approximately 16% of the worlds population; however, little is known regarding the underlying biology of this disorder. Animal studies, postmortem brain analyses and imaging studies of patients with depression have implicated glial dysfunction in MDD pathophysiology. However, the molecular mechanisms through which astrocytes modulate depressive behaviors are largely uncharacterized. Here, we identified ATP as a key factor involved in astrocytic modulation of depressive-like behavior in adult mice. We observed low ATP abundance in the brains of mice that were susceptible to chronic social defeat. Furthermore, we found that the administration of ATP induced a rapid antidepressant-like effect in these mice. Both a lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficiencies in astrocytic ATP release, causing depressive-like behaviors that could be rescued via the administration of ATP. Using transgenic mice that express a Gq G protein–coupled receptor only in astrocytes to enable selective activation of astrocytic Ca2+ signaling, we found that stimulating endogenous ATP release from astrocytes induced antidepressant-like effects in mouse models of depression. Moreover, we found that P2X2 receptors in the medial prefrontal cortex mediated the antidepressant-like effects of ATP. These results highlight astrocytic ATP release as a biological mechanism of MDD.

Fuzi polysaccharide-1 produces antidepressant-like effects in mice

Current antidepressants are clinically effective only after several weeks of administration. We show that Fuzi polysaccharide-1 (FPS), a new water-soluble polysaccharide isolated from Fuzi, which has been used to treat mood disorders in traditional Chinese medicine for centuries, increases the number of newborn cells in the dentate gyrus in adult mice, and most of these cells subsequently differentiate into new neurons. We also found that FPS administration reduces immobility in the forced swim test, and latency in the novelty suppressed-feeding test. Moreover, a 14-d regimen with FPS reverses avoidance behaviour and inhibition of hippocampal neurogenesis induced by chronic defeat stress. In contrast, imipramine, a well known antidepressant, reverses this avoidance behaviour only after 4 wk of continuous administration. Finally, acute treatment with FPS had no effect on brain monoamine levels in frontal cortex but significantly increases BDNF in the hippocampus, while the antidepressant effect and enhancement of cell proliferation induced by FPS administration were totally blocked by K252a, an inhibitor of trkB in a chronic social defeat depression model, suggesting that the neurogenic and antidepressant effects of FPS may involve BDNF signalling. In conclusion, our findings suggest that FPS could be developed as a putative antidepressant with a rapid onset of action.

Astrocytic Adenosine 5′‐Triphosphate Release Regulates the Proliferation of Neural Stem Cells in the Adult Hippocampus

Astrocytes are key components of the niche for neural stem cells (NSCs) in the adult hippocampus and play a vital role in regulating NSC proliferation and differentiation. However, the exact molecular mechanisms by which astrocytes modulate NSC proliferation have not been identified. Here, we identified adenosine 5′‐triphosphate (ATP) as a proliferative factor required for astrocyte‐mediated proliferation of NSCs in the adult hippocampus. Our results indicate that ATP is necessary and sufficient for astrocytes to promote NSC proliferation in vitro. The lack of inositol 1,4,5‐trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficient ATP release from astrocytes. This deficiency led to a dysfunction in NSC proliferation that could be rescued via the administration of exogenous ATP. Moreover, P2Y1‐mediated purinergic signaling is involved in the astrocyte promotion of NSC proliferation. As adult hippocampal neurogenesis is potentially involved in major mood disorder, our results might offer mechanistic insights into this disease. STEM Cells 2013;31:1633–1643

Enhanced excitability in the infralimbic cortex produces anxiety-like behaviors.

The medial prefrontal cortex (mPFC) has been implicated in modulating anxiety. However, it is unknown whether excitatory or inhibitory neurotransmission in the infralimbic (IL) subregion of the mPFC underlies the pathology of anxiety-related behavior. To address this issue, we infused the GABAA receptor (GABAAR) antagonist bicuculline to temporarily activate the IL cortex. IL cortex activation decreased the time spent in the center area in the open field test, decreased exploration of the open-arms in the elevated plus maze test, and increased the latency to bite food in the novelty-suppressed feeding test. These findings substantiate the GABAergic systems role in anxiety-related behaviors. IL cortex inactivation with the AMPA receptor (AMPAR) antagonist CNQX produced opposite, anxiolytic effects. However, infusion of the NMDA receptor (NMDAR) antagonist AP5 into the IL cortex had no significant effect. Additionally, we did not observe motor activity deficits or appetite deficits following inhibition of GABAergic or glutamatergic neurotransmission. Interestingly, we found parallel and corresponding electrophysiological changes in anxious mice; compared to mice with relatively low anxiety, the relatively high anxiety mice exhibited smaller evoked inhibitory postsynaptic currents (eIPSCs) and larger AMPA-mediated evoked excitatory postsynaptic currents (eEPSCs) in pyramidal neurons in the IL cortex. The changes of eIPSCs and eEPSCs were due to presynaptic mechanisms. Our results suggest that imbalances of neurotransmission in the IL cortex may cause a net increase in excitatory inputs onto pyramidal neurons, which may underlie the pathogenic mechanism of anxiety disorders.

Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling

Ion channels are essential for the regulation of neuronal functions. The significance of plasma membrane, mitochondrial, endoplasmic reticulum and lysosomal ion channels in the regulation of Ca2+ is well established. In contrast, surprisingly little is known about the function of ion channels on the nuclear envelope (NE). Here we demonstrate the presence of functional large-conductance, calcium-activated potassium channels (BK channels) on the NE of rodent hippocampal neurons. Functionally, blockade of nuclear BK channels (nBK channels) induces NE-derived Ca2+ release, nucleoplasmic Ca2+ elevation and cyclic AMP response element binding protein (CREB)-dependent transcription. More importantly, blockade of nBK channels regulates nuclear Ca2+–sensitive gene expression and promotes dendritic arborization in a nuclear Ca2+–dependent manner. These results suggest that the nBK channel functions as a molecular link between neuronal activity and nuclear Ca2+ to convey signals from synapse to nucleus and is a new modulator, operating at the NE, of synaptic activity–dependent neuronal functions.

miR-124 Represses ROCK1 Expression to Promote Neurite Elongation Through Activation of the PI3K/Akt Signal Pathway

Recent studies have demonstrated an important role for miR-124, the most abundant and well-conserved brain-specific microRNA(miRNA), in promoting neurite outgrowth and elongation during neuronal differentiation. This miRNA’s target genes and the mechanisms that execute this role remain unclear. In this study, we identified ROCK1, a small GTPase Rho kinase, as a direct target of miR-124 for regulating neurite elongation. miR-124 significantly inhibited ROCK1 expression in M17 cells. Inhibiting ROCK1 promoted neurite elongation, and the overexpression of ROCK1 strongly repressed the neurite elongation-enhancing effect of miR-124 in M17 cells. We determined that Akt functions as a novel ROCK1 downstream effector in regulating neurite outgrowth and elongation.

Mitochondrial BNIP3 upregulation precedes endonuclease G translocation in hippocampal neuronal death following oxygen-glucose deprivation

BackgroundCaspase-independent apoptotic pathways are suggested as a mechanism for the delayed neuronal death following ischemic insult. However, the underlying signalling mechanisms are largely unknown. Recent studies imply the involvement of several mitochondrial proteins, including endonuclease G (EndoG) and Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP3), in the pathway of non-neuronal cells.ResultsIn this report, using western blot analysis and immunocytochemistry, we found that EndoG upregulates and translocates from mitochondria to nucleus in a time-dependent manner in cultured hippocampal neurons following oxygen-glucose deprivation (OGD). Moreover, the translocation of EndoG occurs hours before the observable nuclear pyknosis. Importantly, the mitochondrial upregulation of BNIP3 precedes the translocation of EndoG. Forced expression of BNIP3 increases the nuclear translocation of EndoG and neuronal death while knockdown of BNIP3 decreases the OGD-induced nuclear translocation of EndoG and neuronal death.ConclusionThese results suggest that BNIP3 and EndoG play important roles in hippocampal neuronal apoptosis following ischemia, and mitochondrial BNIP3 is a signal protein upstream of EndoG that can induce neuronal death.

Nitric oxide as an upstream signal of p38 mediates hypoxia/reoxygenation-induced neuronal death.

Nitric oxide (NO) and p38 have been shown to be involved in the ischemia/hypoxia-induced neuronal injury. In this study, we examined the activation patterns of mitogen-activated protein kinases and explored the relationship between NO and p38 in a model of hippocampal neuronal death induced by hypoxia/reoxygenation (H/R). p38 activity increased robustly during hypoxia and after reoxygenation, while the increase of c-Jun amino-terminal kinase and extracellular signal-related kinase activities showed mild tendency. Inhibition of p38 with SB203580 or SB202190 rescued neuronal death, whereas inhibition of extracellular signal-related kinases with PD98059 or c-Jun amino-terminal kinases with SP600125 offered no protection. p38 inhibitors also reduced neuronal death induced by the NO donor S-nitrosoglutathione. L-NAME, a nonspecific NO synthase inhibitor, blocked the p38 activation and rescued H/R-induced neuronal death. These results suggest that NO is an upstream signal of p38 that mediates the H/R-induced neuronal death.

Neuroprotective effects of Xiao-Xu-Ming decoction against ischemic neuronal injury in vivo and in vitro

ETHNOPHARMACOLOGICAL RELEVANCE Xiao-Xu-Ming decoction (XXMD) has long been employed clinically to treat stroke in traditional Chinese Medicine. AIM OF THE STUDY To investigate the neuroprotective effects of XXMD in vivo and in vitro stroke models and determine involved mechanisms. MATERIALS AND METHODS Two models (four-vessel occlusion in adult Wistar rats and oxygen-glucose deprivation primary cultured neurons) were employed to mimic ischemia-reperfusion damage, in vivo and in vitro, respectively. The effects of XXMD were investigated with respect to neuronal damage, activity of caspase-3 and expression of Bcl-2 in CA1 region of hippocampus after ischemia. The cognitive ability was measured 7 days after ischemia/reperfusion by using Morris water maze. RESULTS Oral administration of XXMD significantly increased the density of neurons that survived in the CA1 region of hippocampus on the 3rd and 7th day after transient global ischemia was induced in a dose-dependent manner. XXMD ameliorated severe deficiencies in spatial cognitive performance induced by transient global ischemia. Inhibition of caspase-3 activity and up-regulation of Bcl-2 expression were induced in the high dose of XXMD-treated rats after ischemia. In oxygen-glucose deprivation model, both XXMD extract and drug-containing serum prepared from blood of high dose of XXMD-treated rats inhibited apoptotic neuronal death at 24h after reoxygenation. CONCLUSIONS Our results clearly demonstrated that XXMD is neuroprotective and appears to influence deleterious pathological processes that are activated after the onset of ischemia.

Neuregulin 1 protects against ischemic brain injury via ErbB4 receptors by increasing GABAergic transmission

Identifying novel neuroprotectants that can halt or even reverse the effects of stroke is of interest to both clinicians and scientists. Neuregulin 1 (NRG1) is an effective neuroprotectant, but its molecular mechanisms are largely unclear. In this study, NRG1 rescued cortical neurons from oxygen-glucose deprivation (OGD) model, but the effect was blocked by neutralizing NRG1 and ErbB4 inhibition. In addition, γ-Aminobutyric acid (GABA) receptor agonists had no synergistic effect with NRG1, and the neuroprotective effect of NRG1 against OGD was partly blocked by GABA receptor antagonists. Importantly, NRG1 neuroprotection against brain ischemia was abolished in the mice with specific deletion of ErbB4 in parvalbumin (PV)-positive interneurons. In summary, NRG1 protects against ischemic brain injury via ErbB4 receptors by enhancing GABAergic transmission.