GABA transporters control GABAergic neurotransmission in the mouse subplate
GABA transporters control GABAergic neurotransmission in the mouse subplate
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GABA 转运蛋白控制小鼠亚板中的 GABA 能神经传递
DOI：
10.1016/j.neuroscience.2015.07.067
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发表时间：
2015
期刊：
影响因子：
3.3
通讯作者：
Luhmann HJ
中科院分区：
文献类型：
--
作者：
Unichenko P;Kirischuk S;Luhmann HJ
亚板是发育中的皮质中介于皮质板和中间区之间的过渡层。丘脑-皮质轴突在侵入皮质板之前在亚板神经元（SPns）上形成临时突触。亚板内的神经元活动对于新皮层回路和结构的发育至关重要。虽然SPns上的GABA能和GABA能输入都有报道，但GABA能传递的短期可塑性还没有研究。用全细胞膜片钳技术记录出生后3 - 4天小鼠冠状面新皮层脑片SPns的GABA能突触后电流（GPSC）。诱发的GPSC（eGPSC）引起的电双脉冲刺激表现出双脉冲抑郁症在所有的刺激间隔测试。巴氯芬，一种特异性GABAB受体（GABABR）激动剂，降低eGPSC振幅和增加成对脉冲比（PPR），提示功能性GABABR的突触前定位。选择性GABABR阻断剂（2S）-3-[[（1S）-1-（3，4-二氯苯基）乙基]氨基-2-羟丙基]（苯甲基）次膦酸（CGP 55845）可缓解Bacterium诱导的效应。此外，即使在对照条件下，CGP 55845也增加了eGPSC振幅并降低了PPR，表明GABABR被环境GABA紧张性激活。由于细胞外GABA浓度主要由GABA转运蛋白（GATs）调节，我们问GATs是否释放GABA。1，2，5，6-四氢-1-[2-[[（二苯基亚甲基）氨基]氧基]乙基]-3-吡啶羧酸（NNC-711）（10 μ M），一种选择性GAT-1阻滞剂，可延长eGPSC衰减时间，降低eGPSC振幅和PPR。最后两个效应而不是第一个被CGP 55845阻断，表明GAT-1阻断导致细胞外GABA浓度升高，进而激活突触外GABAAR和突触前GABABR。特异性GAT-2/3阻断剂1-[2-[三（4-甲氧基苯基）甲氧基]乙基]-（S）-3-哌啶羧酸（SNAP-5114）不能影响eGPSC动力学。然而，与NNC-711相比，SNAP-5114增加了eGPSC振幅并降低了PPR。在SNAP-5114存在下，CGP 55845不影响GABA能传递，表明GABABR不再被激活。我们的结论是，在基板GAT-2/3工作在反向模式。通过GAT-2/3释放的GABA激活GABA能突触上的突触前GABABR，并紧张性抑制SPns上的GABA能输入。
The subplate is a transient layer between the cortical plate and intermediate zone in the developing cortex. Thalamo-cortical axons form temporary synapses on subplate neurons (SPns) before invading the cortical plate. Neuronal activity within the subplate is of critical importance for the development of neocortical circuits and architecture. Although both glutamatergic and GABAergic inputs on SPns were reported, short-term plasticity of GABAergic transmission has not been investigated yet. GABAergic postsynaptic currents (GPSCs) were recorded from SPns in coronal neocortical slices prepared from postnatal day 3–4 mice using whole-cell patch-clamp technique. Evoked GPSCs (eGPSCs) elicited by electrical paired-pulse stimulation demonstrated paired-pulse depression at all interstimulus intervals tested. Baclofen, a specific GABABreceptor (GABABR) agonist, reduced eGPSC amplitudes and increased paired-pulse ratio (PPR), suggesting presynaptic location of functional GABABRs. Baclofen-induced effects were alleviated by (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl)phosphinic acid (CGP55845), a selective GABABR blocker. Moreover, CGP55845 increased eGPSC amplitudes and decreased PPR even under control conditions, indicating that GABABRs are tonically activated by ambient GABA. Because extracellular GABA concentration is mainly regulated by GABA transporters (GATs), we asked whether GATs release GABA. 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid (NNC-711) (10 μM), a selective GAT-1 blocker, increased eGPSC decay time, decreased eGPSC amplitudes and PPR. The two last effects but not the first one were blocked by CGP55845, indicating that GAT-1 blockade causes an elevation of extracellular GABA concentration and in turn activation of extrasynaptic GABAARs and presynaptic GABABRs. 1-[2-[tris(4-methoxyphenyl)methoxy]ethyl]-(S)-3-piperidinecarboxylic acid (SNAP-5114), a specific GAT-2/3 blocker, failed to affect eGPSC kinetics. However, in contrast to NNC-711 SNAP-5114 increased eGPSC amplitudes and decreased PPR. In the presence of SNAP-5114 CGP55845 did not influence GABAergic transmission, indicating that GABABRs are not activated any longer. We conclude that in the subplate GAT-2/3 operates in reverse mode. GABA released via GAT-2/3 activates presynaptic GABABRs on GABAergic synapses and tonically inhibits GABAergic inputs on SPns.
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