Passive cable properties of hippocampal CA3 pyramidal neurons

The passive electrical cable properties of CA3 pyramidal neurons from guinea pig hippocampal slices were investigated by applying current steps and recording the voltage transients from 25 CA3 neurons, using a single intracellular microelectrode and a 3-kHz time-share system. Two independent methods were used for estimating the equivalent electrotonic length of the dendrites, L, and the dendritic to somatic conductance ratio, . The first method is similar to that used by Gorman and Mirolli (1972) and gave an average L of 0.96; the average was 2.44. The second method is derived here for the first time and assumes a finite-length cable with lumped soma. It is an exact solution for L and , using the slopes and intercepts of the first two peeled exponentials. The average L was 0.94; the average was 1.51. The results, using both methods, are in close agreement. The average membrane time constant for all 25 CA3 neurons was 23.6 ms, suggesting a large (23,600 cm²) average membrane resistivity. It is concluded that CA3 neurons are electronically short.This work was supported by Grants NS 11535 and NS 15772 from the National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, U.S. Public Health Service.     

Integrative properties of radial oblique dendrites in hippocampal CA1 pyramidal neurons

Although radial oblique dendrites are a major synaptic input site in CA1 pyramidal neurons, little is known about their integrative properties. We have used multisite two-photon glutamate uncaging to deliver different spatiotemporal input patterns to single branches while simultaneously recording the uncaging-evoked excitatory postsynaptic potentials and local Ca2+ signals. Asynchronous input patterns sum linearly in spite of the spatial clustering and produce Ca2+ signals that are mediated by NMDA receptors (NMDARs). Appropriately timed and sized input patterns ( approximately 20 inputs within approximately 6 ms) produce a supralinear summation due to the initiation of a dendritic spike. The Ca2+ signals associated with synchronous input were larger and mediated by influx through both NMDARs and voltage-gated Ca2+ channels (VGCCs). The oblique spike is a fast Na+ spike whose duration is shaped by the coincident activation of NMDAR, VGCCs, and transient K+ currents. Our results suggest that individual branches can function as single integrative compartments.     

Gating properties of single SK channels in hippocampal CA1 pyramidal neurons.

The activation of small-conductance calcium-activated potassium channels (SK) has a profound effect on membrane excitability. In hippocampal pyramidal neurons, SK channel activation by Ca2+ entry from a preceding burst of action potentials generates the slow afterhyperpolarization (AHP). Stimulation of a number of receptor types suppresses the slow AHP, inhibiting spike frequency adaptation and causing these neurons to fire tonically. Little is known of the gating properties of native SK channels in CNS neurons. By using excised inside-out patches, a small-amplitude channel has been resolved that was half-activated by approximately 0.6 microM Ca2+ in a voltage-independent manner. The channel possessed a slope conductance of 10 pS and exhibited nonstationary gating. These properties are in accord with those of cloned SK channels. The measured Ca2+ sensitivity of hippocampal SK channels suggests that the slow AHP is generated by activation of SK channels from a local rise of intracellular Ca2+.     

Inhibition in hippocampal pyramidal neurons during peripheral stimulation

Responses of hippocampal pyramidal neurons were investigated intracellularly in unanesthetized rabbits immobilized with tubocurarine. A single stimulus, applied to the sciatic nerve, evoked prolonged (up to 2.5 sec) hyperpolarization of the cell membrane, accompanied by inhibition of action potentials. The latent period of the evoked hyperpolarization was 48±16.4 msec, and its amplitude 2.5±1.9 mV. In some neurons the development of hyperpolarization potentials was preceded by excitation. The suggestion is made that hyperpolarization of the membrane of pyramidal cells during peripheral stimulation is manifested as an inhibitory postsynaptic potential (IPSP), generated with the participation of hippocampal interneurons. The possibility of prolonged tonic action of interneurons from outside as a cause of prolonged inhibition of the pyramidal neurons is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 1, No. 3, pp. 278–284, November–December, 1969.     

海马锥体神经元树突中电压依赖性钾通道研究进展

海马锥体神经元树突上分布着多种电压依赖性钾离子通道,但这些通道在胞体和树突不同部位的分布密度以及在突触电活动中的功能意义各不相同。倒传递动作电位（b-AP）和兴奋性突触后电位（EPSP）是树突中常见的功能电信号。本文简要介绍了近年来海马锥体神经元树突上这些钾离子通道及其电活动的生理和病理学研究成果。     

Endogenous nature of spontaneous bursting in hippocampal pyramidal neurons

The normal spontaneous bursting behavior of hippocampal pyramidal neurons was investigated. Bursting frequency was found to be membrane potential dependent, the frequency increasing with maintained depolarization and decreasing upon hyperpolarization. Short depolarizing-current pulses would trigger bursts which outlasted the stimulus, and bursting continued when synaptic transmission had been blocked. The spontaneous bursts of these neurons, in contrast to bursts induced by convulsive agents, appear to exhibit the classical behavior of endogenous bursts as observed in invertebrate neurons. The endogenous bursts in hippocampal neurons may result, also, from an interplay of intrinsic membrane currents.     

Membrane electrical properties of mouse hippocampal CA1 pyramidal neurons during strong inputs

In this work, we highlight an electrophysiological feature often observed in recordings from mouse CA1 pyramidal cells that has so far been ignored by experimentalists and modelers. It consists of a large and dynamic increase in the depolarization baseline (i.e., the minimum value of the membrane potential between successive action potentials during a sustained input) in response to strong somatic current injections. Such an increase can directly affect neurotransmitter release properties and, more generally, the efficacy of synaptic transmission. However, it cannot be explained by any currently available conductance-based computational model. Here we present a model addressing this issue, demonstrating that experimental recordings can be reproduced by assuming that an input current modifies, in a time-dependent manner, the electrical and permeability properties of the neuron membrane by shifting the ionic reversal potentials and channel kinetics. For this reason, we propose that any detailed model of ion channel kinetics for neurons exhibiting this characteristic should be adapted to correctly represent the response and the synaptic integration process during strong and sustained inputs.     

Mathematical description of modifying synapses of hippocampal pyramidal neurons

The system of differential equations describing the plasticity of the hippocampal pyramidal neuron CA3, developed before, was analyzed. The system was divided into two groups according to magnitudes of the biochemical reaction constants. The first group with large values of the constants was transformed into quasi stationary algebraic equations. This allowed one to transform the system of 32 differential equations to a system containing only 4 differential equations, which can be used for modeling of learning processes in various parts of the brain.     

海马脑片锥体神经元钙离子通道的盲法膜片钳研究

目的和方法 :采用大鼠海马脑片盲法膜片钳全细胞记录技术研究CA1区锥体神经元电压门控性Ca2 通道的动力学特征。结果 :大鼠海马脑片CA1区锥体神经元电压门控性Ca2 通道电流具有如下特点 :①激活的阈电位偏低 ,为 (- 4 9.3± 8.6 )mV ,范围为 - 6 5～ - 30mV(n =2 3)。②衰减时间常数τ值较大 ,且变化范围大 (10 0～ 70 0ms) (n =12 ) ,并且衰减具有Ca2 电流幅值的依赖性 ,③稳态失活呈现电压依赖性 ,半失活电压为 (- 5 5 .4± 9.7)mV ,斜率因子为 (5 .3± 0 .9)mV(n =10 )。④当细胞外Ca2 浓度为 2 .5mmol/L时 ,Ca2 通道的反转电位为 (5 5±13)mV(n =10 )。⑤尾电流成分较为单一 ,不表现电压依赖性。另外 ,Ca2 电流对戊脉胺及双氢吡啶类化合物硝苯地平均不敏感。结论 :根据上述Ca2 电流特征 ,海马脑片CA1区锥体神经元上的Ca2 通道主要以N型为主     

Enhancement of inward current by serotonin in neurons of Aplysia

In RB cells of Aplysia, serotonin, in the presence of TEA, 4AP and Ba, elicits a voltage-dependent inward current. In Ba-TEA-4AP seawater, RB cells showed a negative slope region (NSR) in their current-voltage (I-V) relationship when measured at the end of 2-s commands from a holding potential of -60 mV. Addition of serotonin to the bathing solution enhanced the NSR. When holding potential was lowered to -10 mV, the NSR as well as the effects of serotonin were greatly reduced. Addition of 20 mM cobalt to the bathing solution blocked both the NSR and the inward current produced by serotonin. Changes in potassium concentration produced no consistent shift in voltage sensitivity nor change in amplitude of the current elicited by serotonin. Intracellular injection of cesium sufficient to broaden action potentials did not block the enhancement of NSR by serotonin. These results support the conclusion that in RB cells, serotonin produces a voltage-dependent current carried by calcium ions.     

Specific enhancement of SK channel activity selectively potentiates the afterhyperpolarizing current I(AHP) and modulates the firing properties of hippocampal pyramidal neurons

SK channels are Ca2+-activated K+ channels that underlie after hyperpolarizing (AHP) currents and contribute to the shaping of the firing patterns and regulation of Ca2+ influx in a variety of neurons. The elucidation of SK channel function has recently benefited from the discovery of SK channel enhancers, the prototype of which is 1-EBIO. 1-EBIO exerts profound effects on neuronal excitability but displays a low potency and limited selectivity. This study reports the effects of DCEBIO, an intermediate conductance Ca2+-activated K+ channel modulator, and the effects of the recently identified potent SK channel enhancer NS309 on recombinant SK2 channels, neuronal apamin-sensitive AHP currents, and the excitability of CA1 neurons. NS309 and DCEBIO increased the amplitude and duration of the apamin-sensitive afterhyperpolarizing current without affecting the slow afterhyperpolarizing current in contrast to 1-EBIO. The potentiation by DCEBIO and NS309 was reversed by SK channel blockers. In current clamp experiments, NS309 enhanced the medium afterhyperpolarization (but not the slow afterhyperpolarization sAHP) and profoundly affected excitability by facilitating spike frequency adaptation in a frequency-independent manner. The potent and specific effect of NS309 on the excitability of CA1 pyramidal neurons makes this compound an ideal tool to assess the role of SK channels as possible targets for the treatment of disorders linked to neuronal hyperexcitability.     

Effects of transmitters on pyramidal and nonpyramidal neurons in hippocampal slices

Investigations were performed on the effects of acetylcholine (ACh), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and -aminobutyric acid (GABA) on the background firing of the three following groups of field CA₃ neurons in guinea pig hippocampal slices: nonpyramidal neurons of the stratum radiatum moleculare (NSR), stratum pyramidale cells with single spike discharges (SD units), and those with complex discharge patterns (CD units) within the same layer. The action of ACh and NE on presumed interneurons of the pyramidal layer (IPL) was also investigated; CD units were found to differ from the remaining groups, which reacted similarly to the transmitters tested. It was shown that NE, 5-HT, and GABA inhibited the activity of CD cells, while ACh produced inhibitory-activating response in 50% of these units. Both NE and ACh exerted a monophasic activating effect on NSR, ISP, and SD, however, while 5-HT and GABA induced activation in a proportion of NSR and SD cells, as well as inhibitory response. The excitatory effects produced by ACh, NE, and 5-HT on NSR persisted during blockade of synaptic transmission, indicating that associated afferent fibers may be acting directly on these cells.Institute of Biological Physics, Academy of Sciences of the USSR, Pushchino-on-Oka. Translated from Neirofiziologiya, Vol. 20, No. 1, pp. 64–74, January–February, 1988.     

Scaling properties of pyramidal neurons in mice neocortex

Dendritic morphology is the structural correlate for receiving and processing inputs to a neuron. An interesting question then is what the design principles and the functional consequences of enlarged or shrinked dendritic trees might be. As yet, only a few studies have examined the effects of neuron size changes. Two theoretical scaling modes have been analyzed, conservative (isoelectrotonic) scaling (preserves the passive and active response properties) and isometric scaling (steps up low pass-filtering of inputs). It has been suggested that both scaling modes were verified in neuroanatomical studies. To overcome obvious limitations of these studies like small size of analyzed samples and restricted validity of utilized scaling measures, we considered the scaling problem of neurons on the basis of large sample data and by employing a more general method of scaling analysis. This method consists in computing the morphoelectrotonic transform (MET) of neurons. The MET maps the neuron from anatomical space into electrotonic space using the logarithm of voltage attenuation as the distance metric. The theory underlying this approach is described and then applied to two samples of morphologically reconstructed pyramidal neurons (cells from neocortex of wildtype and synRas transgenic mice) using the NEURON simulator. In a previous study, we could verify a striking increase of dendritic tree size in synRas pyramidal neurons. Surprisingly, in this study the statistical analysis of the sample MET dendrograms revealed that the electrotonic architecture of these neurons scaled roughly in a MET-conserving mode. In conclusion, our results suggest only a minor impact of the Ras protein on dendritic electroanatomy, with non-significant changes of most regions of the corresponding METs.     

beta-Amyloid increases dendritic Ca2+ influx by inhibiting the A-type K+ current in hippocampal CA1 pyramidal neurons

Accumulation of the beta-amyloid peptide (Abeta) is a primary event in the pathogenesis of Alzheimer's disease (AD). However, the mechanisms by which Abeta mediates neurotoxicity and initiates the degenerative processes of AD are still not clear. Recent evidence shows that voltage-gated K+ channels may be involved in Abeta-induced neurodegenerative processes. In particular, a transient A-type K+ current, with a linear increase in its density with distance from soma to distal dendrites in hippocampal CA1 pyramidal neurons, has been shown to contribute to dendritic membrane excitability. Here, I report that Abeta (1-42) inhibits the dendritic A-type K+ current in hippocampal CA1 pyramidal neurons, and this inhibition causes increases in back-propagating dendritic action potential amplitude and associated Ca2+ influx. These results suggest that the persistent inhibition of the A-type K+ current resulting from deposition of Abeta in dendritic arborization will induce a sustained increase in dendritic Ca2+ influx and lead to loss of Ca2+ homeostasis. This may be a component of the events that cause synaptic failure and initiate neuronal degenerative processes in the hippocampus.     

Field potentials evoked in the subiculum following postsynaptic discharge of hippocampal pyramidal neurons

Evoked potentials, represented by population spikes and slow waves, have been recorded from the subiculum, along its whole dorso-ventral extent, following postsynaptic activation and discharge of hippocampal pyramidal neurons. These potentials can be associated with synaptic excitatory effects generated on radially oriented neurons by hippocampal impulses reaching the subiculum at any dorso-ventral level, according to a segmental organization.     

P物质抑制培养大鼠海马大锥体细胞GABA—激活电流

研究主要探讨P物质（SP）对GABA－激活电流的调制。实验在培养的新生大鼠海马大锥体细胞上进行。应用全细胞膜片箝技术记录GABA激活的内向电流。在被检的大锥体细胞中,有72％（66／92）的神经元对GABA和SP同时敏感,预后SP后,GABA激活电流明显地被抑制,此抑制作用是呈剂量依赖性的。在预加10^-8,10^-7,10^-6,10^-5mol/LSP后,GABA的激活电流分别降低18％,24．8％,25．9％和28％,用SP的拮抗剂 spantide能阻断此种抑制作用,在电极中灌注H7（PKC抑制剂）能取消此抑制作用,上述结果提示：SP对GABA激活电流的抑制作用是SP作用于SP受体,通过胞内第二信使,使GABAA受体通道复合体胞内磷酸化所致。     

Activity-dependent regulation of h channel distribution in hippocampal CA1 pyramidal neurons

The hyperpolarization-activated cation current, I(h), plays an important role in regulating intrinsic neuronal excitability in the brain. In hippocampal pyramidal neurons, I(h) is mediated by h channels comprised primarily of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits, HCN1 and HCN2. Pyramidal neuron h channels within hippocampal area CA1 are remarkably enriched in distal apical dendrites, and this unique distribution pattern is critical for regulating dendritic excitability. We utilized biochemical and immunohistochemical approaches in organotypic slice cultures to explore factors that control h channel localization in dendrites. We found that distal dendritic enrichment of HCN1 is first detectable at postnatal day 13, reaching maximal enrichment by the 3rd postnatal week. Interestingly we found that an intact entorhinal cortex, which projects to distal dendrites of CA1 but not area CA3, is critical for the establishment and maintenance of distal dendritic enrichment of HCN1. Moreover blockade of excitatory neurotransmission using tetrodotoxin, 6-cyano-7-nitroquinoxaline-2,3-dione, or 2-aminophosphonovalerate redistributed HCN1 evenly throughout the dendrite without significant changes in protein expression levels. Inhibition of calcium/calmodulin-dependent protein kinase II activity, but not p38 MAPK, also redistributed HCN1 in CA1 pyramidal neurons. We conclude that activation of ionotropic glutamate receptors by excitatory temporoammonic pathway projections from the entorhinal cortex establishes and maintains the distribution pattern of HCN1 in CA1 pyramidal neuron dendrites by activating calcium/calmodulin-dependent protein kinase II-mediated downstream signals.     

Loss of hippocampal CA3 pyramidal neurons in mice lacking STAM1

STAM1, a member of the STAM (signal transducing adapter molecule) family, has a unique structure containing a Src homology 3 domain and ITAM (immunoreceptor tyrosine-based activation motif). STAM1 was previously shown to be associated with the Jak2 and Jak3 tyrosine kinases and to be involved in the regulation of intracellular signal transduction mediated by interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Here we generated mice lacking STAM1 by using homologous recombination with embryonic stem cells. STAM1(-/-) mice were morphologically indistinguishable from their littermates at birth. However, growth retardation in the third week after birth was observed for the STAM1(-/-) mice. Unexpectedly, despite the absence of STAM1, hematopoietic cells, including T- and B-lymphocyte and other hematopoietic cell populations, developed normally and responded well to several cytokines, including IL-2 and GM-CSF. However, histological analyses revealed the disappearance of hippocampal CA3 pyramidal neurons in STAM1(-/-) mice. Furthermore, we observed that primary hippocampal neurons derived from STAM1(-/-) mice are vulnerable to cell death induced by excitotoxic amino acids or an NO donor. These data suggest that STAM1 is dispensable for cytokine-mediated signaling in lymphocytes but may be involved in the survival of hippocampal CA3 pyramidal neurons.     

Inhibitory processes of hippocampal CA1 pyramidal neurons following kindling-induced epilepsy in the rat

To determine the alterations in cellular function which may contribute to the chronic predisposition of neuronal tissue to epileptiform activity, the membrane properties and inhibitory processes of hippocampal CA1 pyramidal cells were investigated using in vitro slices prepared from commissural-kindled rats. No changes were observed in resting membrane potential, input resistance, spike amplitude, and membrane time constant of "kindled" CA1 pyramidal neurons when compared with controls. There were also no differences between control and kindled preparations in the amplitude of recurrent inhibitory postsynaptic potentials (IPSP) and in the duration of inhibition produced by either alvear (Alv) or stratum radiatum (SR) stimulation. Irrespective of group, repetitive stimulation of the Alv reduced the amplitude of the recurrent IPSP but failed to induce seizurelike activity. On the other hand, repetitive stimulation of SR frequently produced a neuronal burst discharge even though the duration and to some extent the amplitude of orthodromic inhibition was increased. On the basis of these data, it may be suggested that chronic changes in CA1 pyramidal cell membrane properties and transient reductions of inhibitory processes do not underlie the enhanced sensitivity of these neurons to seizure activity associated with kindling.