Min M Y, Melyan Z, Kullmann D M
University Department of Clinical Neurology, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, United Kingdom.
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9932-7. doi: 10.1073/pnas.96.17.9932.
Exogenous application of agonists at the kainate subtype of glutamate receptors has been shown to depress evoked monosynaptic inhibition by gamma-aminobutyric acid (GABA)ergic interneurons in the hippocampus. This observation has led to the hypothesis that synaptic release of endogenous glutamate might have a disinhibitory effect on neuronal circuits, in addition to depolarizing neurons via postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartic acid (NMDA) receptors. It is not known, however, if glutamate released from excitatory neurons has the same kainate receptor-mediated effect on monosynaptic inhibitory transmission as exogenous agonist application. Indeed, the recent demonstration that excitatory synaptic signals elicited in interneurons are partly mediated by kainate receptors suggests that these receptors may have a pro- rather than disinhibitory role. Here, we examine the effect of synaptically released glutamate on monosynaptic inhibitory signaling. In the presence of antagonists to AMPA and NMDA receptors, brief bursts of activity in glutamatergic afferent fibers reduce GABAergic transmission. This depression of inhibition is reversibly abolished by blocking kainate receptors. It persists when GABA(B) receptors are blocked and is enhanced by blocking metabotropic glutamate receptors, possibly explained by presynaptic regulation of glutamate release from excitatory afferents by metabotropic autoreceptors. We conclude that the net kainate receptor-mediated effect of synaptically released glutamate is to reduce monosynaptic inhibition. Since this form of disinhibition may contribute to seizure initiation, kainate receptors may constitute an important target for anticonvulsant drug development.
已表明，在海马体中，外源性应用谷氨酸受体红藻氨酸亚型的激动剂可抑制γ-氨基丁酸（GABA）能中间神经元诱发的单突触抑制。这一观察结果引发了一个假说，即内源性谷氨酸的突触释放除了通过突触后α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）、红藻氨酸和N-甲基-D-天冬氨酸（NMDA）受体使神经元去极化外，可能还对神经回路具有去抑制作用。然而，尚不清楚从兴奋性神经元释放的谷氨酸对单突触抑制性传递是否具有与外源性应用激动剂相同的红藻氨酸受体介导效应。事实上，最近的研究表明，中间神经元中引发的兴奋性突触信号部分由红藻氨酸受体介导，这表明这些受体可能具有促进而非去抑制作用。在这里，我们研究突触释放的谷氨酸对单突触抑制性信号传导的影响。在存在AMPA和NMDA受体拮抗剂的情况下，谷氨酸能传入纤维的短暂活动爆发会降低GABA能传递。通过阻断红藻氨酸受体，这种抑制作用的降低可被可逆性消除。当GABA(B)受体被阻断时，这种抑制作用仍然存在，而通过阻断代谢型谷氨酸受体会增强这种抑制作用，这可能是由于代谢型自身受体对兴奋性传入纤维谷氨酸释放的突触前调节所致。我们得出结论，突触释放的谷氨酸通过红藻氨酸受体介导的净效应是减少单突触抑制。由于这种形式的去抑制可能有助于癫痫发作的起始，红藻氨酸受体可能构成抗惊厥药物开发的重要靶点。
