Astrocytic GABA Receptors in Mouse Hippocampus Control Responses to Behavioral Challenges through Astrocytic BDNF / 神经科学通报·英文版

Major depressive disorder (MDD) is a common mood disorder that affects almost 20% of the global population. In addition, much evidence has implicated altered function of the gamma-aminobutyric acid (GABAergic) system in the pathophysiology of depression. Recent research has indicated that GABA receptors (GABARs) are an emerging therapeutic target in the treatment of stress-related disorders such as MDD. However, which cell types with GABARs are involved in this process is unknown. As hippocampal dysfunction is implicated in MDD, we knocked down GABARs in the hippocampus and found that knocking down these receptors in astrocytes, but not in GABAergic or pyramidal neurons, caused a decrease in immobility in the forced swimming test (FST) without affecting other anxiety- and depression-related behaviors. We also generated astrocyte-specific GABAR-knockout mice and found decreased immobility in the FST in these mice. Furthermore, the conditional knockout of GABARs in astrocytes selectively increased the levels of brain-derived neurotrophic factor protein in hippocampal astrocytes, which controlled the decrease in immobility in the FST. Taken together, our findings contribute to the current understanding of which cell types expressing GABARs modulate antidepressant activity in the FST, and they may provide new insights into the pathological mechanisms and potential targets for the treatment of depression.

Strychnos alkaloids inhibit the proliferation of adult rat neuroprogenitor cells / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the effects of strychnos alkaloids on the proliferation of adult rat neuroprogenitor cells.</p><p><b>METHODS</b>Strychnos alkaloids free of strychnine and brucine were extracted from Strychnos nux vomica, and the effects of Strychnos alkaloids on the survival of HEK293 and PC12 cells were evaluated using MTT assay. In vitro cultured adult rat neuroprogenitor cells isolated from the hippocampus were treated with different concentrations of Strychnos alkaloids for 2 days, and the cell proliferation was assessed using BrdU incorporation assay.</p><p><b>RESULTS</b>At the concentration above 0.5 mg/ml, Strychnos alkaloids produced toxic effect against HEK293 cells (P<0.0001), while for PC12 cells, Strychnos alkaloids inhibited the cell survival at the concentration as low as 5 microg/ml (P<0.0001). After 2 days of exposure to 50 microg/ml Strychnos alkaloids, the neuroprogenitor cells showed significantly decreased number of BrdU-positive cells (P<0.01), but the total cell number remained stable when compared with that of the control cells (P>0.05), whereas at the concentration of 100 microg/ml, Strychnos alkaloids produced obvious cytotoxicity against the neuroprogenitor cells.</p><p><b>CONCLUSION</b>Strychnos alkaloids can significantly inhibit the proliferation of adult rat neuroprogenitor cells, and this effect is probably selective, suggesting the potential of Strychnos alkaloids as a new drug for treatment of neurocytoma.</p>

Developmental changes in synaptic and extrasynaptic N-methyl-D-aspartate receptors in cultured rat hippocampal neurons / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate changes in synaptic and extrasynaptic N-methyl-D-aspartate receptors (NMDAR) during the development of cultured rat hippocampal neurons.</p><p><b>METHODS</b>Synaptic and extrasynaptic NMDAR channel currents were recorded from 1-day-old rat hippocampal neurons cultured for 1 and 2 weeks with patch-clamp technique in whole-cell configuration and outside-out configuration, respectively.</p><p><b>RESULTS</b>The amplitude of NMDAR-mediated miniature excited postsynaptic current (Meps(CNMDA)) decreased in neurons cultured for 2 weeks as compared with that recorded in neurons cultured for 1 week, and the 2-week neurons showed also much lowered sensitivity to selective NR2B blocker ifenprodil. The amplitude and open probability of extrasynaptic NMDAR in the 2-week neurons were significantly higher than those in the 1-week neurons, but the neurons differred little in conduction and reverse potential. Ifenprodil decreased the high conductance and open probability in both neurons, but the effect was more potent in the 2-week ones.</p><p><b>CONCLUSIONS</b>There can be developmental changes in synaptic and extrasynaptic NMDAR channel currents in cultured rat hippocampal neurons, indicating that different NMDAR subtypes are expressed in the synaptic and extrasynaptic regions during the development of the hippocampal neurons. In 1-week neurons, NR2B are predominant both in synaptic and extrasynaptic regions, and at 2 weeks, synaptic NR2B are replaced by NR2A but NR2B still remains the predominant subtypes outside the synapses.</p>