Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated.

At excitatory synapses in the central nervous system, the number of glutamate molecules released from a vesicle is much larger than the number of postsynaptic receptors. But does release of a single vesicle normally saturate these receptors? Answering this question is critical to understanding how the amplitude and variability of synaptic transmission are set and regulated. Here we describe the use of two-photon microscopy to image transient increases in Ca2+ concentration mediated by NMDA (N-methyl-D-aspartate) receptors in single dendritic spines of CA1 pyramidal neurons in hippocampal slices. To test for NMDA-receptor saturation, we compared responses to stimulation with single and double pulses. We find that a single release event does not saturate spine NMDA receptors; a second release occurring 10 ms later produces approximately 80% more NMDA-receptor activation. The amplitude of spine NMDA-receptor-mediated [Ca2+] transients (and the synaptic plasticity which depends on this) may thus be sensitive to the number of quanta released by a burst of action potentials and to changes in the concentration profile of glutamate in the synaptic cleft.     

神经元兴奋性群体峰电位信号的Renyi信息表达

应用时频分布级数分析方法，提取了单次诱发群体峰电位(PS)信号的Renyi信息，并用以表征神经元的兴奋性变化．采用液压打击大鼠脑损伤模型和细胞外记录技术，记录了离体海马脑片CA1区锥体神经元PS，发现损伤侧和非损伤侧PS的Renyi信息参数值差异显著，进而分析了神经元灌流大黄酸后损伤侧PS的Renyi信息参数值的变化，研究大黄酸对神经元的超兴奋性和突触传递的作用．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，大黄酸对神经元的过度兴奋有抑制作用，Renyi信息可作为反映神经元兴奋性变化的一个特征参数．     

虫草素改善脑缺血小鼠学习记忆及保护海马神经元的作用研究

采用双侧颈动脉夹闭建立脑缺血模型,分别观察造模后和造模前腹腔注射100 mg?kg-1虫草素对小鼠Y迷宫行为训练的影响以及检测海马各区神经元数量的变化.结果表明,造模前给予虫草素能明显提高小鼠的正确反应率（p0.05）,减少达标所需训练次数（p0.05）,并显著增加海马CA1区和CA3区锥体神经元数量（p0.01）.造模后给予虫草素对小鼠的正确反应率没有显著影响（p0.05）,但显著减少达标所需训练次数（p0.05）;同时,海马CA3区神经元数量显著增加（p0.01）,而CA1区没有显著变化（p0.05）.由此可见,虫草素能改善脑缺血小鼠的学习能力,预防作用似乎比治疗作用更为显著,其相关机制可能与虫草素促进海马神经元的修复有关.     

Preplay of future place cell sequences by hippocampal cellular assemblies

During spatial exploration, hippocampal neurons show a sequential firing pattern in which individual neurons fire specifically at particular locations along the animal's trajectory (place cells). According to the dominant model of hippocampal cell assembly activity, place cell firing order is established for the first time during exploration, to encode the spatial experience, and is subsequently replayed during rest or slow-wave sleep for consolidation of the encoded experience. Here we report that temporal sequences of firing of place cells expressed during a novel spatial experience occurred on a significant number of occasions during the resting or sleeping period preceding the experience. This phenomenon, which is called preplay, occurred in disjunction with sequences of replay of a familiar experience. These results suggest that internal neuronal dynamics during resting or sleep organize hippocampal cellular assemblies into temporal sequences that contribute to the encoding of a related novel experience occurring in the future.     

Dendritic spikes as a mechanism for cooperative long-term potentiation

Strengthening of synaptic connections following coincident pre- and postsynaptic activity was proposed by Hebb as a cellular mechanism for learning. Contemporary models assume that multiple synapses must act cooperatively to induce the postsynaptic activity required for hebbian synaptic plasticity. One mechanism for the implementation of this cooperation is action potential firing, which begins in the axon, but which can influence synaptic potentiation following active backpropagation into dendrites. Backpropagation is limited, however, and action potentials often fail to invade the most distal dendrites. Here we show that long-term potentiation of synapses on the distal dendrites of hippocampal CA1 pyramidal neurons does require cooperative synaptic inputs, but does not require axonal action potential firing and backpropagation. Rather, locally generated and spatially restricted regenerative potentials (dendritic spikes) contribute to the postsynaptic depolarization and calcium entry necessary to trigger potentiation of distal synapses. We find that this mechanism can also function at proximal synapses, suggesting that dendritic spikes participate generally in a form of synaptic potentiation that does not require postsynaptic action potential firing in the axon.     

A frequency-dependent switch from inhibition to excitation in a hippocampal unitary circuit

The hippocampus, a brain structure essential for memory and cognition, is classically represented as a trisynaptic excitatory circuit. Recent findings challenge this view, particularly with regard to the mossy fibre input to CA3, the second synapse in the trisynaptic pathway. Thus, the powerful mossy fibre input to CA3 pyramidal cells might mediate both synaptic excitation and inhibition. Here we show, by recording from connected cell pairs in rat entorhinal-hippocampal slice cultures, that single action potentials in a dentate granule cell evoke a net inhibitory signal in a pyramidal cell. The hyperpolarization is due to disynaptic feedforward inhibition, which overwhelms monosynaptic excitation. Interestingly, this net inhibitory synaptic response changes to an excitatory signal when the frequency of presynaptic action potentials increases. The process responsible for this switch involves the facilitation of monosynaptic excitatory transmission coupled with rapid depression of inhibitory circuits. This ability to immediately switch the polarity of synaptic responses constitutes a novel synaptic mechanism, which might be crucial to the state-dependent processing of information in associative hippocampal networks.     

组胺能与γ-氨基丁酸能神经传递在间位核神经元信息加工中的作用(英文)

小脑间位核(interpositus nucleus,IN)主要接受γ-氨基丁酸(GABA)能纤维支配,同时接受组胺能纤维的调节.本研究在小脑脑片上研究了GABA和组胺对单个IN神经元电活动的共同作用.持续灌流组胺或同时施加组胺和GABA,81.2%(69/85)神经元,GABA及其激动剂的效应都被组胺削弱(持续灌流n=33;同时施加n=36).这种削弱效应能够被组胺H2受体阻断剂ranitidine(n=10)和PKA抑制剂H-89阻断(n=8),fors-kolin模拟组胺的效应(n=9).结果表明组胺和GABA对IN神经元的电活动具有交互调节作用:通过激活H2受体偶联的G-protein-AC-PKA信号通路,磷酸化GABAB和GABAA受体,降低受体功能.推测受体间的对话的工作模式,可能是整个大脑神经元活动的某些药理作用和生理活动调节的基础;如果对话紊乱,可能导致大脑功能障碍.     

UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis

Microglia, brain immune cells, engage in the clearance of dead cells or dangerous debris, which is crucial to the maintenance of brain functions. When a neighbouring cell is injured, microglia move rapidly towards it or extend a process to engulf the injured cell. Because cells release or leak ATP when they are stimulated or injured, extracellular nucleotides are thought to be involved in these events. In fact, ATP triggers a dynamic change in the motility of microglia in vitro and in vivo, a previously unrecognized mechanism underlying microglial chemotaxis; in contrast, microglial phagocytosis has received only limited attention. Here we show that microglia express the metabotropic P2Y6 receptor whose activation by endogenous agonist UDP triggers microglial phagocytosis. UDP facilitated the uptake of microspheres in a P2Y6-receptor-dependent manner, which was mimicked by the leakage of endogenous UDP when hippocampal neurons were damaged by kainic acid in vivo and in vitro. In addition, systemic administration of kainic acid in rats resulted in neuronal cell death in the hippocampal CA1 and CA3 regions, where increases in messenger RNA encoding P2Y6 receptors that colocalized with activated microglia were observed. Thus, the P2Y6 receptor is upregulated when neurons are damaged, and could function as a sensor for phagocytosis by sensing diffusible UDP signals, which is a previously unknown pathophysiological function of P2 receptors in microglia.     

A physiological role for GABAB receptors in the central nervous system

The role of GABA in synaptic transmission in the mammalian central nervous system is more firmly established than for any other neurotransmitter. With virtually every neuron studied, the synaptic action of GABA is mediated by bicuculline-sensitive GABAA receptors which selectively increase chloride conductance. However, it has been shown that GABA has a presynaptic inhibitory action on transmitter release that is insensiive to bicuculline and is selectively mimicked by baclofen. The receptors involved in this action are referred to as GABAB receptors, to distinguish them from the classic bicuculline-sensitive GABAA receptors. In hippocampal pyramidal cells an additional postsynaptic action of GABA and baclofen has been reported that is also insensitive to GABAA antagonists, and may be mediated by GABAB receptors on the postsynaptic neuron. This action of GABA and baclofen involves an increase in potassium conductance. Synaptic activation of pathways converging on hippocampal pyramidal cells results in a slow inhibitory postsynaptic potential which involves an increase in potassium conductance, and it has been suggested that GABAB receptors might be responsible for this synaptic potential. However, to establish convincingly that GABAB receptors are physiologically important in the central nervous system, a selective GABAB antagonist is required. Here we provide this missing evidence. Using the hippocampal slice preparation, we now report that the phosphonic acid derivative of baclofen, phaclofen, is a remarkably selective antagonist of both the postsynaptic action of baclofen and the bicuculline-resistant action of GABA, and that it selectively abolishes the slow inhibitory postsynaptic potential in pyramidal cells.     

Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons

NMDA (N-methyl-D-aspartate) receptors serve as modulators of synaptic transmission in the mammalian central nervous system (CNS) with both short-term and long-lasting effects. Divalent cations are pivotal in determining this behaviour in that Mg2+ blocks the ion channel in a voltage-dependent manner, and Ca2+ permeates NMDA channels. Zn2+ could also modulate neuronal excitability because it is present at high concentrations in brain, especially the synaptic vesicles of mossy fibers in the hippocampus and is released with neuronal activity. Both proconvulsant and depressant actions of Zn2+ have been reported. We have found that zinc is a potent non-competitive antagonist of NMDA responses on cultured hippocampal neurons. Unlike Mg2+, the effect of Zn2+ is not voltage-sensitive between -40 and +60 mV, suggesting that Zn2+ and Mg2+ act at distinct sites. In addition, we have found that Zn2+ antagonizes responses to the inhibitory transmitter GABA (gamma-aminobutyric acid). Our results provide evidence for an additional metal-binding site on the NMDA receptor channel, and suggest that Zn2+ may regulate both excitatory and inhibitory synaptic transmission in the hippocampus.     

Amyloid β-protein differentially affects NMDA receptor- and GABAA receptor-mediated currents in rat hippocampal CA1 neurons

Although the aggregated amyloid β-protein (Aβ) in senile plaques is one of the key neuropathological features of Alzheimer's disease (AD), soluble forms of Aβ also interfere with synaptic plasticity at the early stage of AD. The suppressive action of acute application of Aβ on hippocampal long-term potentiation (LTP) has been reported widely, whereas the mechanism underlying the effects of Aβ is still mostly unknown. The present study, using the whole-cell patch clamp technique, investigated the effects of Aβ fragments (Aβ25–35 and Aβ31–35) on the LTP induction-related postsynaptic ligand-gated channel currents in isolated hippocampal CA1 neurons. The results showed a rapid but opposite action of both peptides on excitatory and inhibitory receptor currents. Glutamate application-induced currents were suppressed by Aβ25–35 in a dose-dependent manner, and furtherN-methyl-D aspartate(NMDA)receptor-mediated currents were selectively inhibited. In contrast, pretreatment with Aβ fragments potentiated γ-aminobutyric acid (GABA)-induced whole-cell currents. As a control, Aβ35–31, the reversed sequence of Aβ31–35, showed no effect on the currents induced by glutamate,NMDAor GABA. These results may partly explain the impaired effects of Aβ on hippocampal LTP, and suggest that the functional down-regulation of NMDA receptors and up-regulation of GABAA receptors may play an important role in remodeling the hippocampal synaptic plasticity in early AD.     

Sustained firing in auditory cortex evoked by preferred stimuli

It has been well documented that neurons in the auditory cortex of anaesthetized animals generally display transient responses to acoustic stimulation, and typically respond to a brief stimulus with one or fewer action potentials. The number of action potentials evoked by each stimulus usually does not increase with increasing stimulus duration. Such observations have long puzzled researchers across disciplines and raised serious questions regarding the role of the auditory cortex in encoding ongoing acoustic signals. Contrary to these long-held views, here we show that single neurons in both primary (area A1) and lateral belt areas of the auditory cortex of awake marmoset monkeys (Callithrix jacchus) are capable of firing in a sustained manner over a prolonged period of time, especially when they are driven by their preferred stimuli. In contrast, responses become more transient or phasic when auditory cortex neurons respond to non-preferred stimuli. These findings suggest that when the auditory cortex is stimulated by a sound, a particular population of neurons fire maximally throughout the duration of the sound. Responses of other, less optimally driven neurons fade away quickly after stimulus onset. This results in a selective representation of the sound across both neuronal population and time.     

Firing patterns of long-term cultured neuronal network on multi-electrode array

Spontaneous neuronal activity plays an important role in the development and plasticity of brain. To explore the developmental changes in the firing pattern of the neuronal networks in vitro, the hippocampal neurons were cultured on the multi-microelectrode array dish for over 14 weeks and the spontaneous activity was recorded. The results showed that random firing was observed in the 1st week and transformed into synchronized activity after two weeks, then tightly synchronized activity appeared in week 2 to 7 and finally the activities transformed into the random firing pattern. These results suggested three stages in the long-term development of neuronal network in vitro: the stage for connection, the stage of synchronized activity and the mature stage. Synchronized firing shown by spontaneous activity was an important phenomenon in high density cultured neuronal network and transformed patterns during development.     

Glycogenolysis induced by serotonin in brain: identification of a new class of receptor

Serotonin-containing neurones in brain have been proposed to have a role in the control of physiological mechanisms such as sleep, thermoregulation, pain perception and endocrine secretions as well as in the physiopathology of migraine or depressive illness. One difficulty in testing these possibilities lies in the scarcity of pharmacological agents able to interact selectively with the probably multiple classes of serotonin receptors in the central nervous system. Development of such agents would be facilitated by simple in vitro models in which biological responses to serotonin in mammalian brain could be quantified. Thus a serotonin-sensitive adenylate cyclase has been characterized in rat brain, but the response to serotonin is weak in newborn and practically absent in adult animals. In addition, two pharmacologically distinct classes of serotoninergic binding site have been identified using 3H-serotonin and 3H-spiperone as ligands, but their identification as receptors remains to be established. More recently, serotonin has been shown to stimulate phosphorylation of a neuronal protein in slices from the facial motor nucleus, although the receptors mediating this action were not characterized. We now report that serotonin stimulates glycogen hydrolysis in slices of cerebral cortex, that this action is mediated by a novel class of receptors and that tricyclic antidepressants are among the best competitive antagonists of the indolamine.     

Acetylcholine induces burst firing in thalamic reticular neurones by activating a potassium conductance

Recent studies have emphasized the role of acetylcholine (ACh) as an excitatory modulator of neuronal activity in mammalian cortex and hippocampus. Much less is known about the mechanism of direct cholinergic inhibition in the central nervous system or its role in regulating neuronal activities. Here we report that application of ACh to thalamic nucleus reticularis (nRt) neurones, which are known to receive a cholinergic input from the ascending reticular system of the brain stem, causes a hyperpolarization due to a relatively small (1-4 nS) increase in membrane conductance to K+. This cholinergic action appears to be mediated by the M2 subclass of muscarinic receptors and acts in conjunction with the intrinsic membrane properties of nucleus reticularis neurones to inhibit single spike activity while promoting the occurrence of burst discharges. Thus, cholinergic inhibitory mechanisms may be important in controlling the firing pattern of this important group of thalamic neurones.     

基于TMAES对GrC神经元放电活动影响的仿真

经颅磁声电刺激（TMAES）是一种新型无创的脑神经调控技术,具有良好的应用前景.该技术利用静磁场和超声波共同作用所产生的磁声电效应,在神经组织中产生感应电流,进而对神经组织实施刺激.作者基于小脑颗粒细胞模型（GrC模型）,建立了突触连接GrC模型,对TMAES刺激下突触连接GrC模型的动作电位进行仿真,分析了动作电位的传播方向.在TMAES神经元的不同突触连接方式下,对比了兴奋性与抑制性对神经元放电的影响.通过改变抑制点的位置分析了抑制作用在TMAES下对神经元放电模式的影响.仿真结果显示,经颅磁声电刺激对GrC模型神经元放电节律具有重要影响.实现了两个神经元突触连接模型在TMAES下的仿真,对进一步发掘和研究神经元的传导及连接模式具有重要意义.     

组胺能与y-氨基丁酸能神经传递在问位核神经元信息加工中的作用

小脑间位核（interpositusnucleus,IN）主要接受1一氨基丁酸（GABA）能纤维支配,同时接受组胺能纤维的调节．本研究在小脑脑片上研究了GABA和组胺对单个IN神经元电活动的共同作用．持续灌流组胺或同时施加组胺和GABA,81．2％（69／85）神经元,GABA及其激动剂的效应都被组胺削弱（持续灌流n=33;同时施加n=36）．这种削弱效应能够被纽胺H,受体阻断剂ranitidine（n=10）和PK。抑制剂H一89阻断（n=8）,fors—kolin模拟组胺的效应（n=9）．结果表明组胺和GABA对IN神经元的电活动具有交互调节作用：通过激活H：受体偶联的G—protein—AC—PK。信号通路,磷酸化GABAB和GABA^受体,降低受体功能．推测受体间的对话的工作模式,可能是整个大脑神经元活动的某些药理作用和生理活动调节的基础;如果对话紊乱,可能导致大脑功能障碍．     

Comparison of population coherence of place cells in hippocampal subfields CA1 and CA3

The hippocampus, a critical brain structure for navigation, context-dependent learning and episodic memory, is composed of anatomically heterogeneous subregions. These regions differ in their anatomical inputs as well as in their internal circuitry. A major feature of the CA3 region is its recurrent collateral circuitry, by which the CA3 pyramidal cells make excitatory synaptic contacts on each other. In contrast, pyramidal cells in the CA1 region are not extensively interconnected. Although these differences have inspired numerous theoretical models of differential processing capacities of these two regions, there have been few reports of robust differences in the firing properties of CA1 and CA3 neurons in behaving animals. The most extensively studied of these properties is the spatially selective firing of hippocampal 'place cells'. Here we report that in a dynamically changing environment, in which familiar landmarks on the behavioural track and along the wall are rotated relative to each other, the population representation of the environment is more coherent between the original and cue-altered environments in CA3 than in CA1. These results demonstrate a functional heterogeneity between the place cells of CA3 and CA1 at the level of neural population representations.     

电压门控钠离子通道:律动生命乐章的主音符

生命个体传递神经冲动时扩布的电位变化过程以动作电位发放形式为特质表征.电压门控钠离子通道 (voltage-gated sodium channels,VGSCs)是形成动作电位的核心蛋白构件,在细胞的电兴奋产生和律动中起主角作用.VGSCs决定神经元细胞的兴奋性以及从突触输入到轴突输出的信号传导过程.VGSCs也是众...     

Noradrenaline and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current

Neurons in many regions of the mammalian nervous system generate action potentials in two distinct modes: rhythmic oscillations in which spikes cluster together in a cyclical manner, and single spike firing in which action potentials occur relatively independently of one another. Which mode of action potential generation a neuron displays often varies with the behavioural state of the animal. For example, the shift from slow-wave sleep to waking and attentiveness is associated with a change in thalamic neurons from rhythmic burst firing to repetitive single spike activity, and a greatly increased responsiveness to excitatory synaptic inputs. This marked change in firing pattern and excitability is controlled in part by ascending noradrenergic and serotonergic inputs from the brainstem, although the cellular mechanisms of this effect have remained largely unknown. Here we report that noradrenaline and serotonin enhance a mixed Na+/K+ current which is activated by hyperpolarization (Ih) and that this enhancement may be mediated by increases in intracellular concentration of cyclic AMP. This novel action of noradrenaline and serotonin reduces the ability of thalamic neurons to generate rhythmic burst firing and promotes a state of excitability that is conducive to the thalamocortical synaptic processing associated with cognition.