Department of Cell Biology & Anatomy, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
J Neurosci. 2022 May 4;42(18):3768-3782. doi: 10.1523/JNEUROSCI.1914-21.2022. Epub 2022 Mar 24.
Many hippocampal CA1 pyramidal cells function as place cells, increasing their firing rate when a specific place field is traversed. The dependence of CA1 place cell firing on position within the place field is asymmetric. We investigated the source of this asymmetry by injecting triangular depolarizing current ramps to approximate the spatially tuned, temporally diffuse depolarizing synaptic input received by these neurons while traversing a place field. Ramps were applied to CA1 pyramidal neurons from male rats (slice electrophysiology) and (multicompartmental NEURON model). Under control conditions, CA1 neurons fired more action potentials at higher frequencies on the up-ramp versus the down-ramp. This effect was more pronounced for dendritic compared with somatic ramps. We incorporated a four-state Markov scheme for Na1.6 channels into our model and calibrated the spatial dependence of long-term inactivation according to the literature; this spatial dependence was sufficient to explain the difference in dendritic versus somatic ramps. Long-term inactivation reduced the firing frequency by decreasing open-state occupancy, and reduced spike amplitude during trains by decreasing occupancy in the closed state, which comprises the available pool. PKC activator phorbol-dibutyrate, known to reduce Na long-term inactivation, removed spike amplitude attenuation more visibly in dendrites and greatly reduced adaptation, consistent with our hypothesized mechanism. Intracellular application of a peptide inducing long-term Na inactivation elicited spike amplitude attenuation during spike trains in the soma and greatly enhanced adaptation. Our synergistic experimental/computational approach shows that long-term inactivation of Na1.6 is a key mechanism of adaptation in CA1 pyramidal cells. The hippocampus plays an important role in certain types of memory, in part through context-specific firing of "place cells"; these cells were first identified in rodents as being particularly active when an animal is in a specific location in an environment, called the place field of that neuron. In this / study, we found that long-term inactivation of sodium channels causes adaptation in the firing rate that could potentially skew the firing of CA1 hippocampal pyramidal neurons earlier within a place field. A computational model of the sodium channel revealed differential regulation of spike frequency and amplitude by long-term inactivation, which may be a general mechanism for spike frequency adaptation in the CNS.
许多海马 CA1 锥体神经元作为位置细胞发挥作用，当特定的位置场被穿越时，它们的发射率增加。CA1 位置细胞发射率对位置场中位置的依赖性是不对称的。我们通过注入三角形去极化电流斜坡来近似这些神经元在穿越位置场时接收到的空间调谐、时间弥散去极化突触输入，从而研究了这种不对称性的来源。斜坡应用于雄性大鼠的 CA1 锥体神经元 （切片电生理学） 和 （多隔间 NEURON 模型）。在对照条件下，CA1 神经元在上斜坡上比在下斜坡上发射更多的动作电位，频率更高。与体细胞斜坡相比，这种效果在树突上更为明显。我们将钠离子通道的四态 Markov 方案纳入我们的模型，并根据文献校准了长期失活的空间依赖性；这种空间依赖性足以解释树突与体细胞斜坡之间的差异。长期失活通过降低开放状态占有率来降低发射频率，并通过降低关闭状态中的占有率来降低尖峰幅度，这构成了可用池。已知蛋白激酶 C 激活剂佛波醇 -12,13-二丁酸酯可减少钠离子的长期失活，这在树突中更明显地消除了尖峰幅度衰减，并大大降低了适应度，与我们假设的机制一致。细胞内应用诱导钠离子长期失活的肽在体细胞中的尖峰序列中引起尖峰幅度衰减，并大大增强了适应度。我们的协同实验/计算方法表明，钠离子通道的长期失活是 CA1 锥体神经元适应的关键机制。海马在某些类型的记忆中起着重要作用，部分原因是通过“位置细胞”的特定上下文发射；这些细胞最初在啮齿动物中被鉴定为当动物处于环境中的特定位置时特别活跃，称为该神经元的位置场。在这项研究中，我们发现钠离子通道的长期失活会导致发射率的适应，这可能会导致 CA1 海马锥体神经元在位置场中更早地发射。钠离子通道的计算模型揭示了长期失活对尖峰频率和幅度的差异调节，这可能是中枢神经系统尖峰频率适应的一般机制。
