EPSP amplification and the precision of spike timing in hippocampal neurons

The temporal precision with which EPSPs initiate action potentials in postsynaptic cells determines how activity spreads in neuronal networks. We found that small EPSPs evoked from just subthreshold potentials initiated firing with short latencies in most CA1 hippocampal inhibitory cells, while action potential timing in pyramidal cells was more variable due to plateau potentials that amplified and prolonged EPSPs. Action potential timing apparently depends on the balance of subthreshold intrinsic currents. In interneurons, outward currents dominate responses to somatically injected EPSP waveforms, while inward currents are larger than outward currents close to threshold in pyramidal cells. Suppressing outward potassium currents increases the variability in latency of synaptically induced firing in interneurons. These differences in precision of EPSP-spike coupling in inhibitory and pyramidal cells will enhance inhibitory control of the spread of excitation in the hippocampus.     

Dynamic model of neuronal response in the rat hippocampus

A linear lumped model was proposed for the hippocampal CA 1 region of anesthetized rats using differential equations of time-independent coefficients, the afferent and efferent fibers of the alveus as inputs and the averaged evoked potentials (AEPs) and poststimulus time histograms as outputs. The alvear tract, a major efferent path, was proposed to activate interneurons monosynaptically while the anterior alveus activated orthodromically pyramidal cells which then excited the interneurons. The interneurons then inhibited pyramidal cells. The observable field outputs were the excitatory postsynaptic potentials (EPSPs) of interneurons and the inhibitory postsynaptic potentials (IPSPs) of pyramidal cells. Positive neurophysiological feedbacks were proposed among interneurons and among pyramidal cells in order to account for the prolonged time courses of the interneuronal EPSPs and the pyramidal cell IPSPs. The parameters of the model were optimized by a nonlinear regression program which minimized the sum of squared deviations between the model-generated and actual AEPs. The parameters included the temporal dispersion of the input tract (about 3 ms) and the membrane time constant of interneuronal and pyramidal cell populations (4.8 ms). In anesthetized rats, positive feedback gain coefficients were 0.07 among interneurons and 0.85 among pyramidal cells. After a compound spike (I), two postsynaptic AEP components (II and III) of different time courses were detectable at all depths within CA 1 except at the turnover for each component. The hypothesis that the AEP component II was generated by interneurons was tested and confirmed. The quantitative model constitutes a concise construct of the functional organization of the hippocampal CA 1 region, which suggests further theoretical extensions and experimentation.     

L-trans-PDC enhances hippocampal neuronal activity by stimulating glial glutamate release independently of blocking transporters

The glutamate transporter inhibitor, L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) reversibly enhanced hippocampal neuronal activity in the rat and mouse dentate gyrus. The PDC action was still found in mice lacking the glial glutamate transporter GLT-1. PDC did not influence the rate of spontaneous miniature excitatory postsynaptic currents and spontaneous inhibitory postsynaptic currents, ionotropic glutamate receptor currents, or GABA-evoked currents in cultured rat hippocampal neurons. PDC increased glutamate released from cultured hippocampal astrocytes from normal rats, normal mice, and GLT-1 knock-out mice, that is not inhibited by deleting extracellular Na(+), while the drug had no effect on the release from cultured rat hippocampal neurons. The results of the present study thus suggest that PDC stimulates glial glutamate release by a mechanism independent of inhibiting glutamate transporters, which perhaps causes an increase in synaptic glutamate concentrations, in part responsible for the enhancement in hippocampal neuronal activity.     

The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory

Many central neurons possess large acid-activated currents, yet their molecular identity is unknown. We found that eliminating the acid sensing ion channel (ASIC) abolished H(+)-gated currents in hippocampal neurons. Neuronal H(+)-gated currents and transient acidification are proposed to play a role in synaptic transmission. Investigating this possibility, we found ASIC in hippocampus, in synaptosomes, and in dendrites localized at synapses. Moreover, loss of ASIC impaired hippocampal long-term potentiation. ASIC null mice had reduced excitatory postsynaptic potentials and NMDA receptor activation during high-frequency stimulation. Consistent with these findings, null mice displayed defective spatial learning and eyeblink conditioning. These results identify ASIC as a key component of acid-activated currents and implicate these currents in processes underlying synaptic plasticity, learning, and memory.     

Disinhibition Mediates a Form of Hippocampal Long-Term Potentiation in Area CA1

The hippocampus plays a central role in memory formation in the mammalian brain. Its ability to encode information is thought to depend on the plasticity of synaptic connections between neurons. In the pyramidal neurons constituting the primary hippocampal output to the cortex, located in area CA1, firing of presynaptic CA3 pyramidal neurons produces monosynaptic excitatory postsynaptic potentials (EPSPs) followed rapidly by feedforward (disynaptic) inhibitory postsynaptic potentials (IPSPs). Long-term potentiation (LTP) of the monosynaptic glutamatergic inputs has become the leading model of synaptic plasticity, in part due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals. Using whole-cell recording in hippocampal slices from adult rats, we find that the efficacy of synaptic transmission from CA3 to CA1 can be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, we show that the induction of GABAergic plasticity at feedforward inhibitory inputs results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials. Like classic LTP, disinhibition-mediated LTP requires NMDAR activation, suggesting a role in types of learning and memory attributed primarily to the former and raising the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain.     

Alcohol is a potent stimulant of immature neuronal networks: implications for fetal alcohol spectrum disorder

Ethanol consumption during development affects the maturation of hippocampal circuits by mechanisms that are not fully understood. Ethanol acts as a depressant in the mature CNS and it has been assumed that this also applies to immature neurons. We investigated whether ethanol targets the neuronal network activity that is involved in the refinement of developing hippocampal synapses. This activity appears during the growth spurt period in the form of giant depolarizing potentials (GDPs). GDPs are generated by the excitatory actions of GABA and glutamate via a positive feedback circuit involving pyramidal neurons and interneurons. We found that ethanol potently increases GDP frequency in the CA3 hippocampal region of slices from neonatal rats. It also increased the frequency of GDP-driven Ca2+ transients in pyramidal neurons and increased the frequency of GABA(A) receptor-mediated spontaneous postsynaptic currents in CA3 pyramidal cells and interneurons. The ethanol-induced potentiation of GABAergic activity is probably the result of increased quantal GABA release at interneuronal synapses but not enhanced neuronal excitability. These findings demonstrate that ethanol is a potent stimulant of developing neuronal circuits, which might contribute to the abnormal hippocampal development associated with fetal alcohol syndrome and alcohol-related neurodevelopmental disorders.     

Role of an A-Type K+ Conductance in the Back-Propagation of Action Potentials in the Dendrites of Hippocampal Pyramidal Neurons

Action potentials elicited in the axon actively back-propagate into the dendritic tree. During this process their amplitudes can be modulated by internal and external factors. We used a compartmental model of a hippocampal CA1 pyramidal neuron to illustrate how this modulation could depend on (1) the properties of an A-type K⁺ conductance that is expressed at high density in hippocampal dendrites and (2) the relative timing of synaptic activation. The simulations suggest that the time relationship between pre- and postsynaptic activity could help regulate the amplitude of back-propagating action potentials, especially in the distal portion of the dendritic tree.     

动态神经元的网络模型 Ⅰ.模型和算法

从生物神经元接收和处理信息的基本实验事实出发,提出了一种新的神经网络模型。这个模型修改了大多数现有人工神经网络中关于输出函数只反映静态特性的假设,而强调了神经元发放脉冲的动态过程。模型方程分别对应于突触后电位、感受器电位、始段分级电位和轴突上的的脉冲系列,每个方程都具有明确的生理意义。还给出了计算此非线性方程组解的递推算法和程序框图。因此不仅可对本模型作进一步的理论分析,也可在计算机上仿真,并和相应的生物学实验资料进行对照比较。     

动态神经元的网络模型 Ⅰ.模型和算法

从生物神经元接收和处理信息的基本实验事实出发,提出了一种新的神经网络模型。这个模型修改了大多数现有人工神经网络中关于输出函数只反映静态特性的假设,而强调了神经元发放脉冲的动态过程。模型方程分别对应于突触后电位、感受器电位、始段分级电位和轴突上的的脉冲系列,每个方程都具有明确的生理意义。还给出了计算此非线性方程组解的递推算法和程序框图。因此不仅可对本模型作进一步的理论分析,也可在计算机上仿真,并和相应的生物学实验资料进行对照比较。     

Non-Decaying postsynaptics potentials and delayed spikes in hippocampal pyramidal neurons generated by a zero slope conductance created by the persistent Na+ current

The negative slope conductance created by the persistent sodium current (I_NaP) prolongs the decay phase of excitatory postsynaptic potentials (EPSPs). In a recent study, we demonstrated that this effect was due to an increase of the membrane time constant. When the negative slope conductance opposes completely the positive slope conductances of the other currents it creates a zero slope conductance region. In this region the membrane time constant is infinite and the decay phase of the EPSPs is virtually absent. Here we show that non-decaying EPSPs are present in CA1 hippocampal pyramidal cells in the zero slope conductance region, in the suprathreshold range of membrane potential. Na⁺ channel block with tetrodotoxin abolishes the non-decaying EPSPs. Interestingly, the non-decaying EPSPs are observed only in response to artificial excitatory postsynaptic currents (aEPSCs) of small amplitude, and not in response to aEPSCs of big amplitude. We also observed concomitantly delayed spikes with long latencies and high variability only in response to small amplitude aEPSCs. Our results showed that in CA1 pyramidal neurons I_NaP creates non-decaying EPSPs and delayed spikes in the subthreshold range of membrane potentials, which could potentiate synaptic integration of synaptic potentials coming from distal regions of the dendritic tree.     

Variability of neurotransmitter concentration and nonsaturation of postsynaptic AMPA receptors at synapses in hippocampal cultures and slices

To understand the elementary unit of synaptic communication between CNS neurons, one must know what causes the variability of quantal postsynaptic currents and whether unitary packets of transmitter saturate postsynaptic receptors. We studied single excitatory synapses between hippocampal neurons in culture. Focal glutamate application at individual postsynaptic sites evoked currents (I(glu)) with little variability compared with quantal excitatory postsynaptic currents (EPSCs). The maximal I(glu) was >2-fold larger than the median EPSC. Thus, variations in [glu]cleft are the main source of variability in EPSC size, and glutamate receptors are generally far from saturation during quantal transmission. This conclusion was verified by molecular antagonism experiments in hippocampal cultures and slices. The general lack of glutamate receptor saturation leaves room for increases in [glu]cleft as a mechanism for synaptic plasticity.     

Disentanglement of local field potential sources by independent component analysis

The spontaneous activity of working neurons yields synaptic currents that mix up in the volume conductor. This activity is picked up by intracerebral recording electrodes as local field potentials (LFPs), but their separation into original informative sources is an unresolved problem. Assuming that synaptic currents have stationary placing we implemented independent component model for blind source separation of LFPs in the hippocampal CA1 region. After suppressing contaminating sources from adjacent regions we obtained three main local LFP generators. The specificity of the information contained in isolated generators is much higher than in raw potentials as revealed by stronger phase-spike correlation with local putative interneurons. The spatial distribution of the population synaptic input corresponding to each isolated generator was disclosed by current-source density analysis of spatial weights. The found generators match with axonal terminal fields from subtypes of local interneurons and associational fibers from nearby subfields. The found distributions of synaptic currents were employed in a computational model to reconstruct spontaneous LFPs. The phase-spike correlations of simulated units and LFPs show laminar dependency that reflects the nature and magnitude of the synaptic currents in the targeted pyramidal cells. We propose that each isolated generator captures the synaptic activity driven by a different neuron subpopulation. This offers experimentally justified model of local circuits creating extracellular potential, which involves distinct neuron subtypes.     

Coherent phasic excitation during hippocampal ripples

High-frequency hippocampal network oscillations, or "ripples," are thought to be involved in episodic memory. According to current theories, memory traces are represented by assemblies of principal neurons that are activated during ripple-associated network states. Here we performed in?vivo and in?vitro experiments to investigate the synaptic mechanisms during ripples. We discovered postsynaptic currents that are phase-locked to ripples and coherent among even distant CA1 pyramidal neurons. These fast currents are consistent with excitatory postsynaptic currents (EPSCs) as they are observed at the equilibrium potential of Cl(-), and they display kinetics characteristic of EPSCs. Furthermore, they survived after intracellular blockade of GABAergic transmission and are effective to regulate the timing of action potentials. In addition, our data show a progressive synchronization of phasic excitation and inhibition during the course of ripples. Together, our results demonstrate the presence of phasic excitation during ripples reflecting an exquisite temporal coordination of assemblies of active pyramidal cells.     

Elementary polysynaptic potentials of hippocampal neurons

Synaptic connections of 26 pairs of hippocampal neurons were studied in nonanesthetized rabbits by spike-triggered averaging of intracellularly recorded activity. Synchronized activity was detected in 5 pairs and considered to represent common inputs to the neurons recorded. Hyperpolarizing or depolarizing potentials with 3--4 ms latency were revealed in 3 additional pairs. These potentials are considered to be individual postsynaptic potentials (PSPs) evoked in the target neuron by spikes of the adjacent (0.5--2 mm apart) neuron. A quantum analysis of the individual PSPs was performed. The mean quantum content (0.27--0.65) and quantum size (35--200 mkV) were found to be of the same order as those of the excitatory PSPs previously recorded after intracerebral stimulation. It is concluded that most hippocampal synapses are of low efficacy.     

Synchronized Ca2+ signals mediated by Ca2+ action potentials in the hippocampal neuron network in vitro

Periodic, synchronized Ca2+ signals appeared 30-120 min after the application of tetrodotoxin, 4-aminopyridine and Cs+, and became stable in interval (6-47s) for hours. The Ca2+ signals were accompanied by excitatory or inhibitory postsynaptic potentials (excitatory postsynaptic currents (EPSCs) for the former) and blocked by the simultaneous application of 6-cyano-7-nitroquinoxaline-2,3-dione and 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid or treatment with Ca2+ -free solution, nicardipine, or omega-conotoxin MVIIC (omegaCTX), but not with ryanodine, caffeine, thapsigargin or CPP alone. Nicardipine largely, but omegaCTX less, blocked Ca2+ action potentials or voltage pulse-induced Ca2+ currents at the cell soma, while omegaCTX completely blocked autaptic EPSCs. Ca2+ signals within a neuron occurred almost simultaneously in the cell soma and all the processes (> 200 microm), while the latency between Ca2+ signals of neighbouring neurons varied over hundreds of ms like that of Ca2 action potential induction from EPSPs. Ca2+ signals propagated in random directions throughout neural circuits. Thus, when Na+ and K+ channels are blocked, Ca2+ action potentials spontaneously occur somewhere in a neuron, eventually propagate via the cell soma to the presynaptic terminals and activate excitatory synaptic transmission, causing synchronized Ca2+ signals. The results further suggest that the axon of hippocampal neurones have the potential ability to convey coded information via Ca2+ action potentials.     

Synaptic transmission in slices of rat hippocampus using a modified voltage clamp technique

A small modification to a voltage-clamp set-up for studying isolated neurons, and the use of simple hippocampal slices allowed stable recording of excitatory postsynaptic currents (EPSCs) that were evoked by stimulating the Shaffer's collaterals of individual CA1 pyramidal neurons. With the developed method EPSCs and focal extracellular potentials could be recorded simultaneously. It was confirmed that the EPSC consists of two components that are mediated via N-methyl-D-aspartate (NMDA)- and non-NMDA-receptors. The effects of different blockers of these receptors on the postsynaptic current were investigated, as were the effects of adenosine, which, depending on its concentration, could either depress or potentiate the synaptic transmission.A. A. Bogomolets Institute of Physiology, Ukrainian Academy of Sciences, Kiev. Translated from Neirofiziologiya, Vol. 23, No. 6, pp. 731–738, November–December, 1991.     

液压打击损伤后海马CA1区神经元兴奋性变化的研究

为考察脑损伤对海马CA1区锥体神经元电活动的影响并研究大黄素对神经元的超兴奋性和突触传递的作用,应用液压打击大鼠脑损伤模型和细胞外记录方法提取诱发的海马CA1区场兴奋性突触后电位(fPSP)和群峰电位(PS),进行相关的数据处理和分析。发现损伤侧比非损伤侧的fPSP斜率明显升高,PS波峰个教显著增加,而PS潜伏期明显减小;在灌流液中施加大黄素,CA1区诱发场电位明显减弱。研究结果表明：颅脑损伤可造成海马CA1区锥体神经元的迟发性过度兴奋;大黄素对神经元的兴奋性有抑制作用,可能对颅脑损伤后的中枢神经系统具有保护功能。     

Effects of rectification on synaptic efficacy.

We have investigated the effects of postsynaptic membrane properties on the shape of synaptic potentials generated by time-varying synaptic conductances. We used numerical simulation techniques to model cells of several different geometrical forms, from an isopotential sphere to a neuron with a soma and a dendritic tree. A variety of postsynaptic membrane properties were tested: (a) a passive resistance-capacitance membrane, (b) a membrane represented by the Hodgkin and Huxley (HH) equations, and (c) a membrane that was passive except for a delayed rectification represented by a voltage- and time-dependent increase in GK. In all cases we investigated the effects of these postsynaptic membrane properties on synaptic potentials produced by synaptic conductances that were fast or slow compared with the membrane time constant. In all cases the effects of postsynaptic rectification occurred on postsynaptic potentials of amplitudes as low as 1 mV. The HH model (compared with the passive model) produced an increased peak amplitude (from the increase in GNa) but a decreased half-width and a decreased time integral (from the increase in GK). These effects of the HH GK change were duplicated by a simple analytical rectifier model.     

Selective activation of field CA1-CA2 by perforant neurons discharging in response to hippocampal efferent volleys

A long lasting evoked response, generated in the hippocampal field CA1-CA2 following postsynaptic sequential discharge of hippocampal pyramids and entorhinal neurons, has been analyzed by multiple simultaneous surface and depth recordings in the guinea pig dorsal hippocampal region. Results obtained suggest that it can be associated with postsynaptic excitatory potentials evoked in the distal portion of the apical dendrites of field CA1-CA2 pyramids by perforant neurons selectively discharged by impulses of hippocampal origin.     

Molecular and functional characterization of the electroneutral Na/HCO3 cotransporter NBCn1 in rat hippocampal neurons

We examined molecular and electrophysiological properties of the electroneutral sodium/bicarbonate cotransporter (NBCn1) that is present in rat hippocampal neurons. By PCR, a deletion variant (NBCn1-E) that lacks 123 amino acids in the cytoplasmic N-terminal domain was found in adult neurons. The previously characterized NBCn1-B, which does not have the deletion, was detected in embryonic neurons. In Xenopus oocytes, NBCn1-E raised the intracellular pH in the presence of HCO(3) without significantly affecting the membrane potential. Despite this electroneutral cotransport activity, the transporter mediated a steady-state current that positively shifted the resting potential by almost 30 mV. The mean reversal potential of the steady-state current was -21.2 mV, close to the resting potential of -21.4 mV. The reversal potential shifted 26 mV in response to a 10-fold increase of external Na(+) for concentrations above 10 mm. The current activity mediated by the transporter was unaffected by K(+), Mg(2+), Ca(2+), or Cl(-). Stable expression of NBCn1-E in human embryonic kidney cells also evoked an inward current that shifted the resting potentials more positive compared with the sham-transfected controls. In primary cultures of embryonic hippocampal neurons, the NBCn1 protein was localized in somatodendrites and synapses. NBCn1 protein was partially colocalized with the postsynaptic density protein PSD-95. Single-cell PCR showed that NBCn1 mRNA expression was present in both gamma-aminobutyric acid (GABA)ergic and non-GABAergic neurons. We propose that NBCn1 in hippocampal neurons may affect neuronal activity by regulating local pH as well as steady-state inward currents at synapses.