Riekki Ruusu, Pavlov Ivan, Tornberg Janne, Lauri Sari E, Airaksinen Matti S, Taira Tomi
Neuroscience Center, University of Helsinki, Helsinki, Finland.
J Neurophysiol. 2008 Jun;99(6):3075-89. doi: 10.1152/jn.00606.2007. Epub 2008 Apr 24.
GABA(A) receptor (GABA-AR)-mediated inhibition is critical for proper operation of neuronal networks. Synaptic inhibition either shifts the membrane potential farther away from the action potential firing threshold (hyperpolarizing inhibition) or via increase in the membrane conductance shunts the excitatory currents. However, the relative importance of these different forms of inhibition on the hippocampal function is unclear. To study the functional consequences of the absence of hyperpolarizing inhibition, we have used KCC2-deficient mice (KCC2hy/null) maintaining only 15-20% of the neuron-specific K-Cl-cotransporter. Gramicidin-perforated patch-clamp recordings in hippocampal CA1 pyramidal cells revealed that the reversal potential of the GABA-AR-mediated postsynaptic currents (E(GABA-A)) was approximately 20 mV more positive in KCC2hy/null mice than in wild-type (WT) animals. The basic glutamatergic transmission appeared unaltered in the KCC2hy/null mice, yet they displayed lowered threshold for stimulation-induced synchronous afterdischarges in the CA1 area. Also fatigue of field excitatory postsynaptic potentials/excitatory postsynaptic currents in response to repetitious stimulation was smaller in KCC2hy/null mice, indicating altered synaptic dynamics. Interestingly, this effect was present also under blockade of GABA-ARs and was dependent on the extracellular K+ concentration. Moreover, there were no differences in the levels of either long-term potentiation or long-term depression between the genotypes. The local hippocampal CA1 network can in several aspects maintain its functional viability even in the absence of hyperpolarizing inhibition in pyramidal cells. Our results underscore the central role of shunting type of inhibition in controlling the neuronal excitation/inhibition balance. Moreover, our data demonstrate a novel, unexpected role for the KCC2, namely the modulation of properties of glutamatergic transmission during repetitious afferent activity.
γ-氨基丁酸A型受体（GABA(A)受体，GABA-AR）介导的抑制作用对于神经网络的正常运作至关重要。突触抑制要么使膜电位远离动作电位发放阈值（超极化抑制），要么通过增加膜电导分流兴奋性电流。然而，这些不同形式的抑制作用对海马功能的相对重要性尚不清楚。为了研究超极化抑制缺失的功能后果，我们使用了KCC2基因缺陷小鼠（KCC2hy/null），其仅保留15%-20%的神经元特异性钾氯共转运体。海马CA1锥体神经元的短杆菌肽穿孔膜片钳记录显示，与野生型（WT）动物相比，KCC2hy/null小鼠中GABA-AR介导的突触后电流（E(GABA-A)）的反转电位正移约20 mV。KCC2hy/null小鼠的基本谷氨酸能传递似乎未改变，但它们在CA1区的刺激诱导同步后放电阈值降低。此外，KCC2hy/null小鼠对重复刺激的场兴奋性突触后电位/兴奋性突触后电流的疲劳程度较小，表明突触动力学发生改变。有趣的是，这种效应在GABA-AR阻断时也存在，并且依赖于细胞外钾离子浓度。此外，不同基因型之间在长时程增强或长时程抑制水平上没有差异。即使锥体神经元中不存在超极化抑制，局部海马CA1网络在几个方面仍能维持其功能活性。我们的结果强调了分流型抑制在控制神经元兴奋/抑制平衡中的核心作用。此外，我们的数据证明了KCC2的一个新的、意想不到的作用，即在重复传入活动期间对谷氨酸能传递特性的调节。
