Presynaptic kainate receptors in the hippocampus: slowly emerging from obscurity.

Kainate receptor agonists depress transmitter release at several synapses in the hippocampus. Distinct mechanisms appear to underlie this phenomenon at different synapses. Recently, it has emerged that presynaptic kainate receptors can also potentiate the release of both GABA and glutamate and that axonal kainate receptors can trigger ectopic action potentials in interneurons. Because synaptically released glutamate mimics many of the actions of exogenous agonists, presynaptic kainate receptors potentially play an extensive role in hippocampal signaling.     

Synaptic localization of adrenergic disinhibition in the rat hippocampus.

Norepinephrine is an endogenous neurotransmitter that reduces synaptic inhibition onto pyramidal neurons in the hippocampus by an action at an alpha-adrenergic receptor. The physiological mechanism of this disinhibition was previously not known, except that it occurred at a site presynaptic to the inhibited pyramidal cell. In this paper we present evidence that adrenergic disinhibition is restricted to the early phase of the evoked inhibitory postsynaptic potential in area CA1 of the hippocampus. The locus of disinhibition does not appear to reside in the interneuronal terminal, axon, or cell body. Instead, adrenergic agonists appear to reduce evoked synaptic inhibition by depressing excitatory synapses that activate the interneuron.     

Further studies of the effects of somatostatin and related peptides in area CA1 of rabbit hippocampus

1. In slice studies of mature and immature CA1 hippocampal pyramidal cells from rabbit, somatostatin 14 (SS14), the related peptide somatostatin 28(1-12) [SS(1-12)], and the synthetic analogue of somatostatin 14, SMS-201995 (SMS), had similar effects. When pressure-ejected onto cell somata, these peptides elicited depolarizations, often accompanied by action potential discharge. When applied to dendrites, the peptides produced depolarizations or hyperpolarizations. 2. When a large amount of one of the three somatostatin-related (SS) peptides was applied to the slice at some distance from the impaled cell, hyperpolarizations were observed that were not always blocked by tetrodotoxin (TTX) or low Ca2+. Since SS peptides were also found to depolarize interneurons in area CA1, it seems likely that the hyperpolarizations that were blocked by TTX or low Ca2+ were mediated via excitation of interneurons that in turn hyperpolarized pyramidal cells. 3. All SS peptides also had long-lasting effects on CA1 pyramidal cells that led to spontaneous firing of action potentials and an increase in the number of action potentials discharged in response to a given depolarizing current pulse; the spontaneous discharge effect was blocked by TTX or low Ca2+ plus Mn2+ and, thus, appeared to have a presynaptic mechanism. However, the increase in discharge in response to a constant depolarizing current pulse was not dependent on intact synaptic transmission and, therefore, was attributable to a direct postsynaptic effect of the SS peptides.     

Subunit composition of kainate receptors in hippocampal interneurons

Kainate receptor activation affects GABAergic inhibition in the hippocampus by mechanisms that are thought to involve the GluR5 subunit. We report that disruption of the GluR5 subunit gene does not cause the loss of functional KARs in CA1 interneurons, nor does it prevent kainate-induced inhibition of evoked GABAergic synaptic transmission onto CA1 pyramidal cells. However, KAR function is abolished in mice lacking both GluR5 and GluR6 subunits, indicating that KARs in CA1 stratum radiatum interneurons are heteromeric receptors composed of both subunits. In addition, we show the presence of presynaptic KARs comprising the GluR6 but not the GluR5 subunit that modulate synaptic transmission between inhibitory interneurons. The existence of two separate populations of KARs in hippocampal interneurons adds to the complexity of KAR localization and function.     

Action Potential Modulation in CA1 Pyramidal Neuron Axons Facilitates OLM Interneuron Activation in Recurrent Inhibitory Microcircuits of Rat Hippocampus

Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outside-out patch recordings from CA1 pyramidal neuron axons revealed a high density of α-dendrotoxin (α-DTX)-sensitive, inactivating K⁺ channels, suggesting that K⁺ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron–O-LM interneuron excitatory postsynaptic currents (EPSCs) showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K⁺ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron–interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.     

Complex events initiated by individual spikes in the human cerebral cortex

Synaptic interactions between neurons of the human cerebral cortex were not directly studied to date. We recorded the first dataset, to our knowledge, on the synaptic effect of identified human pyramidal cells on various types of postsynaptic neurons and reveal complex events triggered by individual action potentials in the human neocortical network. Brain slices were prepared from nonpathological samples of cortex that had to be removed for the surgical treatment of brain areas beneath association cortices of 58 patients aged 18 to 73 y. Simultaneous triple and quadruple whole-cell patch clamp recordings were performed testing mono- and polysynaptic potentials in target neurons following a single action potential fired by layer 2/3 pyramidal cells, and the temporal structure of events and underlying mechanisms were analyzed. In addition to monosynaptic postsynaptic potentials, individual action potentials in presynaptic pyramidal cells initiated long-lasting (37 ± 17 ms) sequences of events in the network lasting an order of magnitude longer than detected previously in other species. These event series were composed of specifically alternating glutamatergic and GABAergic postsynaptic potentials and required selective spike-to-spike coupling from pyramidal cells to GABAergic interneurons producing concomitant inhibitory as well as excitatory feed-forward action of GABA. Single action potentials of human neurons are sufficient to recruit Hebbian-like neuronal assemblies that are proposed to participate in cognitive processes.     

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.     

Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity

This study reveals mechanisms in the mouse hippocampus that may underlie nicotinic influences on attention, memory, and cognition. Induction of synaptic plasticity, arising via generally accepted mechanisms, is modulated by nicotinic acetylcholine receptors. Properly timed nicotinic activity at pyramidal neurons boosted the induction of long-term potentiation via presynaptic and postsynaptic pathways. On the other hand, nicotinic activity on interneurons inhibited nearby pyramidal neurons and thereby prevented or diminished the induction of synaptic potentiation. The synaptic modulation was dependent on the location and timing of the nicotinic activity. Loss of these synaptic mechanisms may contribute to the cognitive deficits experienced during Alzheimer's diseases, which is associated with a loss of cholinergic projections and with a decrease in the number of nicotinic receptors.     

Distinct cannabinoid sensitive receptors regulate hippocampal excitation and inhibition

One of the well-known effects of cannabinoids is the impairment of cognitive processes, including short-term memory formation, by altering hippocampal and neocortical functions reflected in network activity. Acting on presynaptically located G protein-coupled receptors in the hippocampus, cannabinoids modulate the release of neurotransmitter molecules. CB1 cannabinoid receptors, so far the only cloned cannabinoid receptor type in the CNS, are selectively expressed on the axon terminals of a subset of GABAergic inhibitory interneurons containing the neuropeptide cholecystokinin. Activation of CB1 receptors reduces GABA release from presynaptic terminals, thereby increasing the excitability of principal cells. Novel, non-CB1 cannabinoid sensitive receptors are present on the hippocampal excitatory axon terminals, which suppress glutamate release. These cannabinoid receptors have distinct pharmacological features compared to CB1, i.e. WIN 55212-2 is an order of magnitude less potent in reducing glutamatergic transmission than in inhibiting GABAergic postsynaptic currents, and the novel receptor binds vanilloid receptor ligands. Thus, at least two different cannabinoid sensitive presynaptic receptors regulate network activity in the hippocampus, CB1 via the GABAergic interneurons, and a new receptor via a direct action on pyramidal cell axon terminals.     

突触前α7烟碱受体对海马神经元兴奋性突触传递的调控

采用盲法膜片钳技术观察突触前烟碱受体(nicotinic acetylcholinel receptors,nAChRs)对海马脑片CAl区锥体神经元兴奋性突触传递的调控作用。结果显示,nAChRs激动剂碘化二甲基苯基哌嗪(dimethylphenyl—piperazinium iodide,DMPP)不能在CAl区锥体神经元上诱发出烟碱电流。DMPP对CAl区锥体神经元自发兴奋性突触后电流(spontaneous excitatory postsynaptic current,sEPSC)具有明显的增频和增幅作用,并呈现明显的浓度依赖关系。DMPP对微小兴奋性突触后电流(miniature excitatory postsynaptic current,mEPSC)具有增频作用,但不具有增幅作用。上述DMPP增强突触传递的作用不能被nAChRs拮抗剂美加明、六烃季铵和双氢-β-刺桐丁所阻断,但可被α-银环蛇毒素阻断。上述结果提示,海马脑片CAl区锥体神经元兴奋性突触前nAChRs含有对α-银环蛇毒素敏感的胡亚单位,其激活可增强海马CAl区锥体神经元突触前递质谷氨酸的释放,从而对兴奋性突触传递发挥调控作用。     

大鼠海马脑中枝形吊灯样中间神经元的形态与电生理学特征

在大鼠海马脑片标本上,用微电极记录并标记了４个枝形吊灯样中间,约占所记录到的３９个中间神经元的１０％,与蓝状中间神经元显著不同之处是,这４个神经元均对细胞内去极化电流表现出不同程度的放电频率适应现象,用细胞内注射ｂｉｏｃｙｔｉｎ的方法证实,蓝状中间神经元轴突终末主要分布在锥体在颗粒细胞层,与这些细胞胞体形成接触,而４个枝形吊灯样中间神经元的轴突终末增高度选择性分布在锥体和颗粒细胞轴突始段区,上述结     

AVP_（4－8）结合点在大鼠海马内的分布和AVP_（4－8）对其受体发育的影响：放射自显影研究

本文利用放射自显影方法结合神经毒对海马神经元的选择性损毁观察ＡＶＰ（４－８）结合点在大鼠海马内的分布和定位;利用外源性ＡＶＰ（４－８）对新生大鼠的处理,观察海马ＡＶＰ（４－８）结合点的发育调节。在成年大鼠海马内,ＡＶＰ（４－８）结合点集中分布在整个海马的锥体细胞层和齿回的颗粒细胞层。秋水仙碱处理后,齿回颗粒细胞层消失,齿回区的ＡＶＰ（４－８）结合点也消失。红藻氨酸（Ｋａｉｎｉｃａｃｉｄ）处理后海马ＣＡ３－ＣＡ４的锥体细胞层消失,该区的ＡＶＰ（４－８）结合点也消失。新生大鼠海马锥体细胞层的ＡＶＰ（４－８）结合点在出生后第６天开始出现,齿回颗粒细胞层的ＡＶＰ（４－８）结合点在出生后第７天开始出现。然而,新生大鼠每天经外源性ＡＶＰ（４－８）处理,海马锥体细胞层和齿回颗粒细胞层的结合点均在出生后第５天已变得十分稠密。本文就大鼠海马ＡＶＰ（４－８）结合点的特异性分布和ＡＶＰ（４－８）处理促进海马ＡＶＰ（４－８）结合点的发育与成年后大鼠学习能力的提高的相互关系作了讨论。     

神经元对于高频电刺激的动态响应

深部脑刺激(deep brain stimulation,DBS)在许多神经系统疾病的临床治疗上都展现出良好的应用前景,然而,其作用机制尚不明确.常规DBS采用高频刺激(high frequency stimulation,HFS)的脉冲序列,这种窄脉冲最容易激活神经元结构中的轴突部分,通过轴突的投射,将HFS的作用传播至下游神经元.因此,为了探讨DBS的作用机制,并鉴于海马脑区是治疗癫痫和痴呆症等疾病的重要靶点,我们研究了海马区轴突HFS对于下游神经元的作用.对麻醉大鼠的海马CA1区传入神经通路Schaffer侧支施加1 min的100 Hz高频刺激,记录并提取下游CA1区锥体神经元和中间神经元的单元锋电位.计算锋电位的发放率,以及它们与刺激脉冲之间的锁相值(phase-locking value,PLV)和潜伏期,以定量分析HFS期间神经元动作电位发放的变化趋势.结果显示,在传入轴突上施加HFS时,初期会诱发下游神经元群体同步产生动作电位(即群峰电位).在HFS后期(群峰电位消失之后),两类神经元的单元锋电位发放仍然持续,并且发放率较稳定.但是,锋电位与刺激脉冲之间的锁相性逐渐减弱、潜伏期逐渐延长.而且,与中间神经元相比较,锥体神经元锋电位的锁相性更弱、潜伏期更长.这些结果表明,持续的轴突HFS可以诱导下游神经元产生非同步的活动,高频脉冲刺激引起的不完全轴突传导阻滞可能是导致该现象产生的主要原因.本文的研究为揭示脑刺激的作用机制提供了重要信息.     

Oscillatory neural networks in the rabbit hippocampus

A model is described to account for damped oscillatory activity of two interacting neural populations, pyramidal cells and interneurons. This network in the hippocampus is treated as a lumped system with tine delays between elements. The physiological mechanism underlying the oscillatory activity appears to involve neural population interaction and cannot be described in terms of a network composed of but two neurons, a single pyramidal cell and a single interneuron. An unusual aspect of the model is the explicit incorporation of an ongoing background input to raise the mean level of activity of the pyramidal cell population. This model has evolved from a series of studies previously performed on cats. To test the model experiments were performed on rabbits. The data showing oscillatory activity following fornix stimulation in the rabbit indicate that the model can be applied not only to the cat but also to the rabbit. In additions, for commissural stimulation oscillatory potentials of neural populations and individual pyramidal cells were evoked as predicted by the model.     

Mouse Delta Opioid Receptors are Located on Presynaptic Afferents to Hippocampal Pyramidal Cells

Delta opioid receptors participate in the control of chronic pain and emotional responses. Recent data have also identified their implication in drug-context associations pointing to a modulatory role on hippocampal activity. We used fluorescent knock-in mice that express a functional delta opioid receptor fused at its carboxy terminus with the green fluorescent protein in place of the native receptor to investigate the receptor neuroanatomical distribution in this structure. Fine mapping of the pyramidal layer was performed in hippocampal acute brain slices and organotypic cultures using fluorescence confocal imaging, co-localization with pre- and postsynaptic markers and correlative light-electron microscopy. The different approaches concurred to identify delta opioid receptors on presynaptic afferents to glutamatergic principal cells. In the latter, only scarce receptors were detected that were confined within the Golgi or vesicular intracellular compartments with no receptor present at the cell surface. In the mouse hippocampus, expression of functional delta opioid receptors is therefore mostly associated with interneurons emphasizing a presynaptic modulatory effect on the pyramidal cell firing rate.     

mGluRs Modulate Strength and Timing of Excitatory Transmission in Hippocampal Area CA3

Excitatory transmission within hippocampal area CA3 stems from three major glutamatergic pathways: the perforant path formed by axons of layer II stellate cells in the entorhinal cortex, the mossy fiber axons originating from the dentate gyrus granule cells, and the recurrent axon collaterals of CA3 pyramidal cells. The synaptic communication of each of these pathways is modulated by metabotropic glutamate receptors that fine-tune the signal by affecting both the timing and strength of the connection. Within area CA3 of the hippocampus, group I mGluRs (mGluR1 and mGluR5) are expressed postsynaptically, whereas group II (mGluR2 and mGluR3) and III mGluRs (mGluR4, mGluR7, and mGluR8) are expressed presynaptically. Receptors from each group have been demonstrated to be required for different forms of pre- and postsynaptic long-term plasticity and also have been implicated in regulating short-term plasticity. A recent observation has demonstrated that a presynaptically expressed mGluR can affect the timing of action potentials elicited in the postsynaptic target. Interestingly, mGluRs can be distributed in a target-specific manner, such that synaptic input from one presynaptic neuron can be modulated by different receptors at each of its postsynaptic targets. Consequently, mGluRs provide a mechanism for synaptic specialization of glutamatergic transmission in the hippocampus. This review will highlight the variability in mGluR modulation of excitatory transmission within area CA3 with an emphasis on how these receptors contribute to the strength and timing of network activity within pyramidal cells and interneurons.     

Spike-triggered dendritic calcium transients depend on synaptic activity in the cricket giant interneurons.

The relationship between electrical activity and spike-induced Ca2+ increases in dendrites was investigated in the identified wind-sensitive giant interneurons in the cricket. We applied a high-speed Ca2+ imaging technique to the giant interneurons, and succeeded in recording the transient Ca2+ increases (Ca2+ transients) induced by a single action potential, which was evoked by presynaptic stimulus to the sensory neurons. The dendritic Ca2+ transients evoked by a pair of action potentials accumulated when spike intervals were shorter than 100 ms. The amplitude of the Ca2+ transients induced by a train of spikes depended on the number of action potentials. When stimulation pulses evoking the same numbers of action potentials were separately applied to the ipsi- or contra-lateral cercal sensory nerves, the dendritic Ca2+ transients induced by these presynaptic stimuli were different in their amplitude. Furthermore, the side of presynaptic stimulation that evoked larger Ca2+ transients depended on the location of the recorded dendritic regions. This result means that the spike-triggered Ca2+ transients in dendrites depend on postsynaptic activity. It is proposed that Ca2+ entry through voltage-dependent Ca2+ channels activated by the action potentials will be enhanced by excitatory synaptic inputs at the dendrites in the cricket giant interneurons.     

Calretinin-containing interneurons innervate both principal cells and interneurons in the CA1 region of the human hippocampus

Hippocampal interneurons consist of functionally diverse cell types, most of them target the dendrites or perisomatic region of pyramidal cells with a few exceptions, like the calretinin-containing cells in the rat: they selectively innervate other interneurons. However, no electron microscopic data are available about the synaptic connections of calretinin-immunoreactive neurons in the human hippocampus. We aimed to provide these data to establish whether interneuron-selective interneurons indeed represent an essential feature of hippocampal circuits across distant species. Two types of calretinin-immunostained terminals were found in the CA1 region: one of them presumably derived from the thalamic reuniens nucleus, and established asymmetric synapses on dendrites and spines. The other type originating from local interneurons formed symmetric synapses on both pyramidal and interneuron dendrites. Distribution of postsynaptic targets showed that 26.8% of the targets were CR-positive interneuron dendrites, and 25.2% proved to be proximal pyramidal dendrites. CR-negative interneuron dendrites were also contacted (12.4%). Small caliber postsynaptic dendrites were not classified (28%). Somata were rarely contacted (7.6%). The present data suggest that calretinin-positive boutons do show a preference for other interneurons, but a considerable proportion of the targets are pyramidal cells. We propose that interneuron-selective inhibitory cells exist in the human Ammon's horn, and boutons innervating pyramidal cells derive from another cell type that might not exist in rodents.     

Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes

Endocannabinoids and their receptor CB1 play key roles in brain function. Astrocytes express CB1Rs that are activated by endocannabinoids released by neurons. However, the consequences of the endocannabinoid-mediated neuron-astrocyte signaling on synaptic transmission are unknown. We show that endocannabinoids released by hippocampal pyramidal neurons increase the probability of transmitter release at CA3-CA1 synapses. This synaptic potentiation is due to CB1R-induced Ca(2+) elevations in astrocytes, which stimulate the release of glutamate that activates presynaptic metabotropic glutamate receptors. While endocannabinoids induce synaptic depression in the stimulated neuron by direct activation of presynaptic CB1Rs, they indirectly lead to synaptic potentiation in relatively more distant neurons by activation of CB1Rs in astrocytes. Hence, astrocyte calcium signal evoked by endogenous stimuli (neuron-released endocannabinoids) modulates synaptic transmission. Therefore, astrocytes respond to endocannabinoids that then potentiate synaptic transmission, indicating that astrocytes are actively involved in brain physiology.