Meeks Julian P, Mennerick Steven
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 2004 Jan 7;24(1):197-206. doi: 10.1523/JNEUROSCI.4845-03.2004.
High-frequency synaptic transmission is depressed by moderate rises in the extracellular potassium concentration ([K+]o). Previous reports have indicated that depression of action potential signaling may underlie the synaptic depression. Here, we investigated the specific contribution of K+-induced action potential changes to synaptic depression. We found that glutamatergic transmission in the hippocampal area CA1 was significantly depressed by 8-10 mM [K+]o, but that GABAergic transmission remained intact. Riluzole, a drug that slows recovery from inactivation of voltage-gated sodium channels (NaChs), interacts with subthreshold [K+]o to depress afferent volleys and EPSCs strongly. Thus, elevated [K+]o likely depresses synapses by slowing NaCh recovery from inactivation. It is unclear from previous studies whether [K+]o-induced action potential depression is caused by changes in initiation, reliability, or waveform. We investigated these possibilities explicitly. [K+]o-induced afferent volley depression was independent of stimulus strength, suggesting that changes in action potential initiation do not explain [K+]o-induced depression. Measurements of action potentials from single axons revealed that 8 mM [K+]o increased conduction failures in a subpopulation of fibers and depressed action potential amplitude in all fibers. Together, these changes quantitatively account for the afferent volley depression. We estimate that conduction failure explains more than half of the synaptic depression observed at 8 mM [K+]o, with the remaining depression likely explained by waveform changes. These mechanisms of selective sensitivity of glutamate release to [K+]o accumulation represent a unique neuromodulatory mechanism and a brake on runaway excitation.
细胞外钾离子浓度（[K⁺]o）适度升高会抑制高频突触传递。先前的报告表明，动作电位信号的抑制可能是突触抑制的基础。在此，我们研究了钾离子诱导的动作电位变化对突触抑制的具体作用。我们发现，海马CA1区的谷氨酸能传递在[K⁺]o为8 - 10 mM时显著受到抑制，但γ-氨基丁酸能传递保持完整。利鲁唑是一种能减缓电压门控钠通道（NaChs）从失活状态恢复的药物，它与阈下[K⁺]o相互作用，强烈抑制传入冲动和兴奋性突触后电流（EPSCs）。因此，升高的[K⁺]o可能通过减缓NaCh从失活状态的恢复来抑制突触。从先前的研究中尚不清楚[K⁺]o诱导的动作电位抑制是由起始、可靠性还是波形的变化引起的。我们明确研究了这些可能性。[K⁺]o诱导的传入冲动抑制与刺激强度无关，这表明动作电位起始的变化并不能解释[K⁺]o诱导的抑制。对单个轴突动作电位的测量显示，8 mM [K⁺]o增加了一部分纤维中的传导失败，并降低了所有纤维的动作电位幅度。这些变化共同定量地解释了传入冲动抑制。我们估计，传导失败解释了在8 mM [K⁺]o时观察到的超过一半的突触抑制，其余的抑制可能由波形变化解释。谷氨酸释放对[K⁺]o积累的这种选择性敏感机制代表了一种独特的神经调节机制和对失控兴奋的一种抑制。
