Search

Action potentials are fundamental to relaying information from region to region in the nervous system. Changes in action potential firing patterns in neural circuits influence how the brain processes information. In our previous study, we focused on interneuron/perineuronal astrocyte pairs in the hippocampal CA1 region and reported that direct depolarization of perineuronal astrocytes modulated the firing pattern of interneurons. In the current study, we investigated the morphological and electrophysiological properties of perineuronal oligodendrocytes, and examined their modulatory effects on interneuronal firing in the CA1 region. Perineuronal oligodendrocytes only had a few processes, which were crooked, intricately twisted, and twined around the soma and proximal region of the main processes of adjacent interneurons. Whole-cell current patterns of perineuronal oligodendrocytes were homogenous and the current-voltage relationship showed remarkable outward rectification. Although the K channel blockers, tetraethylammonium and 4-aminopyridine, clearly blocked outward currents, Ba did not significantly alter whole-cell currents. Unlike perineuronal astrocytes, the depolarization of perineuronal oligodendrocytes had no effect on interneuronal firing; however, when the interneurons were firing at a higher frequency, the hyperpolarization of perineuronal oligodendrocytes suppressed their action potentials. The suppressive effects of perineuronal oligodendrocytes were inhibited in the presence of a low concentration of tetraethylammonium, which selectively blocked deep and fast afterhyperpolarization. These results suggest that perineuronal oligodendrocytes suppress interneuronal firing through their influence on K channels, which are responsible for deep and fast afterhyperpolarization. [ABSTRACT FROM AUTHOR]

Diacylglycerol kinase (DGK) plays a key role in pathophysiological cellular responses by regulating the levels of a lipid messenger diacylglycerol. Of DGK isozymes, DGKζ localizes to the nucleus in various cells such as neurons. We previously reported that DGKζ translocates from the nucleus to the cytoplasm in hippocampal CA1 pyramidal neurons after 20 min of transient forebrain ischemia. In this study, we examined the underlying mechanism of DGKζ translocation using hippocampal slices exposed to oxygen-glucose deprivation (OGD) to simulate an ischemic model of the brain. DGKζ-immunoreactivity gradually changed from the nucleus to the cytoplasm in CA1 pyramidal neurons after 20 min of OGD and was never detected in the nucleus after reoxygenation. Intriguingly, DGKζ was detected in the nucleus at 10 min OGD whereas the following 60 min reoxygenation induced complete cytoplasmic translocation of DGKζ. Morphometric analysis revealed that DGKζ cytoplasmic translocation correlated with nuclear shrinkage indicative of an early process of neuronal degeneration. The translocation under OGD conditions was blocked by NMDA receptor (NMDAR) inhibitor, and was induced by activation of NMDAR. Chelation of the extracellular Ca blocked the translocation under OGD conditions. These results show that DGKζ cytoplasmic translocation is triggered by activation of NMDAR with subsequent extracellular Ca influx. Furthermore, inhibition of PKC activity under OGD conditions led to nuclear retention of DGKζ in about one-third of the neurons, suggesting that PKC activity partially regulates DGKζ cytoplasmic translocation. These findings provide clues to guide further investigation of glutamate excitotoxicity mechanisms in hippocampal neurons. [ABSTRACT FROM AUTHOR]

Gangliosides (sialic acid-containing glycosphingolipids) play important roles in many physiological functions, including synaptic plasticity in the hippocampus, which is considered as a cellular mechanism of learning and memory. In the present study, three types of synaptic plasticity, long-term potentiation (LTP), long-term depression (LTD) and reversal of LTP (depotentiation, DP), in the field excitatory post-synaptic potential in CA1 hippocampal neurons and learning behavior were examined in β1,4-N-acetylgalactosaminyltransferase (β1,4 GalNAc-T; GM2/GD2 synthase) gene transgenic (TG) mice, which showed a marked decrease in b-pathway gangliosides (GQ1b, GT1b and GD1b) in the brain and isolated hippocampus compared with wild-type (WT) mice. The magnitude of the LTP induced by tetanus (100 pulses at 100 Hz) in TG mice was significantly smaller than that in control WT mice, whereas there was no difference in the magnitude of the LTD induced by three short trains of low-frequency stimulation (LFS) (200 pulses at 1 Hz) at 20 min intervals between the two groups of mice. The reduction in the LTP produced by delivering three trains of LFS (200 pulses at 1 Hz, 20 min intervals) was significantly greater in the TG mice than in the WT mice. Learning was impaired in the four-pellet taking test (4PTT) in TG mice, with no significant difference in daily activity or activity during the 4PTT between TG and WT mice. These results suggest that the overexpression of β1,4 GalNAc-T resulted in altered synaptic plasticity of LTP and DP in hippocampal CA1 neurons and learning in the 4PTT, and this is attributable to the shift from b-pathway gangliosides to a-pathway gangliosides. [ABSTRACT FROM PUBLISHER]

Abstract: Long-term potentiation (LTP) at hippocampal mossy fiber-CA3 pyramidal neuron synapses was induced in the field excitatory postsynaptic potential (EPSP) by the delivery of HFS (a tetanus of two trains of 100 pulses at 100Hz with a 10s interval) and was reversed (depotentiated) by a train of LFS of 1000 pulses at 2Hz applied 60min later. This depotentiation was triggered by activation of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) during HFS, which may increase the postsynaptic intracellular Ca2+ concentration, leading to a cellular process responsible for modification of LTP expression at mossy fiber-CA3 synapses. Furthermore, we found that activation of IP3Rs or protein phosphatase during LFS was required for the reversal of LTP expressed at mossy fiber-CA3 synapses. These results suggest that, in hippocampal mossy fiber-CA3 neuron synapses, activation of IP3Rs by a preconditioning HFS results in modulation of IP3R activation and/or postsynaptic protein phosphorylation during a subsequent LFS, leading to a decrease in the field EPSP and the erasure of LTP. [Copyright &y& Elsevier]

Abstract: In the present study, mice lacking the type 1 inositol-1,4,5-trisphosphate receptor (IP3R) were used to study the role of type 1 IP3Rs in the induction of long-term potentiation (LTP) in hippocampal CA1 neurons. The magnitude of the LTP induced by high frequency stimulation (HFS) consisting of 20 pulses at 30Hz in mice lacking type 1 IP3Rs was significantly larger than that in wild-type mice in terms of the field excitatory postsynaptic potential and population spike. By measuring changes in the intracellular Ca2+ concentration ([Ca2+]i) in CA1 pyramidal neurons using fluorometry, we found that the decay time of the transient increase in the [Ca2+]i evoked by the HFS in mutant mice was significantly longer than that in wild-type mice, whereas the [Ca2+]i at rest and the magnitude of the [Ca2+]i increases caused by the HFS were no different from those in wild-type mice. In slices from the mutant mice, paired-pulse stimulation (PPS) delivered at an interval of 10ms resulted in significantly weaker paired-pulse inhibition (PPI) than in wild-type mice, suggesting that lack of type 1 IP3Rs reduces the PPI induced by PPS in the CA1 region. These results indicate that a lack of type 1 IP3Rs causes a slower decay of the transient [Ca2+]i in CA1 pyramidal neurons and attenuates the activity of inhibitory interneurons, resulting in enhancement of LTP induction. [Copyright &y& Elsevier]

Hippocampal inhibitory interneurons have a central role in the control of network activity, and excitatory synapses that they receive express Hebbian and anti-Hebbian long-term potentiation (LTP). Because many interneurons in the hippocampus express nicotinic acetylcholine receptors (nAChRs), we explored whether exposure to nicotine promotes LTP induction in these interneurons. We focussed on a subset of interneurons in the stratum oriens/alveus that were continuously activated in the presence of nicotine due to the expression of non-desensitizing non-α7 nAChRs. We found that, in addition to α2 subunit mRNAs, these interneurons were consistently positive for somatostatin and neuropeptide Y mRNAs, and showed morphological characteristics of oriens-lacunosum moleculare cells. Activation of non-α7 nAChRs increased intracellular Ca2+ levels at least in part via Ca2+ entry through their channels. Presynaptic tetanic stimulation induced N-methyl-d-aspartate receptor-independent LTP in voltage-clamped interneurons at −70 mV when in the presence, but not absence, of nicotine. Intracellular application of a Ca2+ chelator blocked LTP induction, suggesting the requirement of Ca2+ signal for LTP induction. The induction of LTP was still observed in the presence of ryanodine, which inhibits Ca2+ -induced Ca2+ release from ryanodine-sensitive intracellular stores, and the L-type Ca2+ channel blocker nifedipine. These results suggest that Ca2+ entry through non-α7 nAChR channels is critical for LTP induction. Thus, nicotine affects hippocampal network activity by promoting LTP induction in oriens-lacunosum moleculare cells via continuous activation of non-α7 nAChRs. [ABSTRACT FROM AUTHOR]

Oligodendrocytes have received much attention in relation to neurological and psychiatric disorders. The involvement of oligodendrocytes and their myelin in normal brain functions has been suggested by many lines of evidence. The conduction velocity of action potentials along axons is dramatically increased by myelination, that is, the formation of a passive insulator. There is a growing understanding of the functional roles of ion channels and neurotransmitter receptors on oligodendrocytes, and the activity-dependent facilitative effect of oligodendrocytes on conduction velocity has been demonstrated. In this article, we summarize evidence for the ability of oligodendrocytes to monitor neuronal activity and for the facilitation of axonal conduction by oligodendrocytes by mechanisms other than myelination. We suggest the underlying mechanisms for this facilitation in relation to the morphological dynamics of myelinating processes and discuss the physiological roles of the facilitation in information processing. [ABSTRACT FROM AUTHOR]

We have previously reported that acute and chronic nicotine exposure lower the threshold for long-term potentiation (LTP) induction in the rat hippocampal CA1 region, and acute application of nicotine in the chronic-nicotine-treated hippocampus further reduces the threshold. However, it is unknown how withdrawal from chronic nicotine exposure affects the induction of LTP. Here, we show that, following nicotine withdrawal, the threshold for LTP induction fluctuates before returning to the basal level and acute nicotine is no longer effective in lowering the threshold at 4 days after withdrawal. Chronic nicotine-induced enhancement of N-methyl-d-aspartate receptor responses slowly diminishes and returns to the control level by 8 days of withdrawal. In 4-day-withdrawn hippocampi, there is functional up-regulation of postsynaptic α7 nicotinic acetylcholine receptors (nAChRs) on interneurons in the stratum radiatum, whereas the release of γ-aminobutyric acid from their terminals is reduced. In both control and chronic nicotine-exposed hippocampi, acute nicotine depresses monosynaptic inhibitory postsynaptic currents recorded in pyramidal cells but has almost no effect at 4 days of withdrawal. The lack of effect is due, at least in part, to the loss of a presynaptic nicotine effect. These withdrawal-induced changes are accompanied by decreases in normal nicotine-induced enhancement of N-methyl-d-aspartate receptor responses, which may be responsible for the lack of acute nicotine-mediated facilitation of LTP induction in 4-day-withdrawn hippocampi. These withdrawal-induced changes may contribute to the cellular basis of unpleasant withdrawal symptoms and, thus, nicotine dependence. [ABSTRACT FROM AUTHOR]

The use of nicotine via cigarette smoking forms long-lasting memories that are recalled in response to environmental cues associated with previous nicotine use. However, the changes in brain memory systems that underlie these long-lasting memories are not well understood. The N-methyl-d-aspartate receptor (NMDAR) is critical for long-lasting modifications of synapses. Here we show that in vivo nicotine exposure induces the enhancement of NR2B-containing NMDAR-mediated currents in the hippocampus, a brain region associated with the formation of memories. This nicotine effect is maintained during continued nicotine exposure and is accompanied by increased tyrosine phosphorylation of NR2B. Furthermore, long-term potentiation (LTP), which is considered to be a cellular substrate of learning and memory, induced in nicotine-exposed hippocampi contains a protein synthesis-independent long-lasting component. An NR2B-selective antagonist blocks a long-lasting component of LTP, but not LTP. These results suggest that exposure to nicotine provides conditions that promote the induction of long-lasting modifications of synapses, which may be involved in the formation of memories involving nicotine use. [ABSTRACT FROM AUTHOR]

Nicotine facilitates the induction of long-term potentiation (LTP) in the hippocampal CA1 region. The present study reveals the potential mechanisms underlying this effect of nicotine. Timed ACh-mediated activation of α7 nicotinic acetylcholine receptors (nAChRs) on pyramidal cells is known to promote LTP induction. Nicotine could suppress this timing-dependent mechanism by desensitizing nAChRs. Timed ACh-mediated activation of α7 nAChRs on feedforward interneurons can prevent LTP induction by inhibiting pyramidal cells. Nicotine diminished this ACh-mediated inhibition by desensitizing α7 nAChRs, thereby reducing the inhibitory influence on pyramidal cells. In addition to these desensitizing effects, nicotine activated presynaptic non-α7 nAChRs on feedforward interneurons to decrease the evoked release of γ-aminobutyric acid (GABA) onto pyramidal cells. Furthermore, nicotine increased the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) in pyramidal cells, and concomitantly caused a reduction in the size of responses to focal GABA application onto the dendrites of pyramidal cells, suggesting that the nicotine-induced increase in interneuronal activity leads ultimately to a use-dependent depression of evoked IPSCs in pyramidal cells. These nicotine-induced suppressions of inhibition of pyramidal cells were accompanied by enhanced N-methyl- d-aspartate (NMDA) responses in pyramidal cells. Thus, our results suggest that nicotine promotes the induction of LTP by diminishing inhibitory influences on NMDA responses while suppressing the ACh-mediated mechanisms. These ACh-independent mechanisms probably contribute to the nicotine-induced cognitive enhancement observed in the presence of cholinergic deficits, such as those in Alzheimer's disease patients. [ABSTRACT FROM AUTHOR]

Long-term potentiation (LTP) in the hippocampal CA1 region is widely regarded to be the cellular substrate of learning and memory, and its induction critically depends on the activation of N-methyl-d-aspartate receptors (NMDARs). Nicotine reverses memory deficits caused by a lesion of the cholinergic system in animals. The mechanisms underlying this effect and the effect of nicotine on LTP after cholinergic degeneration are unknown. Here we show that cholinergic lesions impaired the induction of LTP, and nicotine reversed this effect and promoted the induction of LTP. The compensatory action of nicotine appears to be due to the enhancement of NMDAR responses mediated by nicotine-induced disinhibition of pyramidal cells. This may represent the cellular basis of nicotine-mediated cognitive enhancement observed in the presence of cholinergic deficits. [Copyright &y& Elsevier]

The perfusion of adenosine triphosphate (ATP) induces long-term potentiation (LTP) in CA1 synapses of hippocampal slices, whereas the perfusion of ATP plus d,l-2-amino-5-phosphonovaleric acid (AP5) can result in the formation of long-term depression (LTD). To clarify the difference in change of intracellular calcium concentration ([Ca2+]i) corresponding to induction of LTP or LTD, we measured [Ca2+]i during the perfusion of ATP or ATP+AP5, while simultaneously recording evoked field potentials. In both cases, ATP (or ATP+AP5) perfusion transiently increased [Ca2+]i but the extent of increase of [Ca2+]i by ATP was larger than that caused by ATP+AP5. Thus, the larger rise in [Ca2+]i induces LTP but the smaller rise induces LTD. These results are consistent with the Ca2+ hypothesis as proposed by Lisman (Trends Neurosci. 17 (1994) 406). [Copyright &y& Elsevier]

The neuromodulator acetylcholine (ACh) is considered to have a crucial effect on sensory inputs in the process of learning and memory, and ACh activates muscarinic (mAChR) and nicotinic (nAChR) acetylcholine receptors. Meanwhile in a hippocampal CA1 network including inhibitory connections, long-term potentiation (LTP) or long-term depression (LTD) is induced by the application of positive timing of the spike timing-dependent plasticity (STDP) protocol, while LTD is induced by negative timing protocol. In the previous study, the influence of ACh on LTD induced by the negative timing protocol application in the interneuron-blocked CA1 network was reported. However, the responsibility of mAChR and nAChR on pyramidal neuron and interneuron on STDP induction is still unclear. In order to clarify the role of AChRs in LTD, positive or negative timing protocol was applied in the interneuron-activated CA1 network in the presence of eserine. Consequently, the LTD induced by the positive timing protocol was switched to LTP, and the LTD by negative timing protocol was shifted toward potentiation when ACh was effective. The STDP facilitation was more effectively brought by mAChR activation on pyramidal neuron than nAChR, while mAChR on interneuron had a potential to down regulate the facilitation. These findings suggest that the direction (LTD/LTP) of STDP is determined by the activation of mAChR not only on pyramidal neuron but also on interneuron, and the magnitude of STDP is sensitively fine-tuned by nAChR. Therefore, the modulation of synaptic plasticity induced by the coactivation of mAChR and nAChR might be an important stage in integrating ACh and sensory inputs in the hippocampal CA1 network. [ABSTRACT FROM AUTHOR]

In CA1 neurons of guinea pig hippocampal slices, long-term depression (LTD) was induced in the field EPSP response in the absence of test synaptic inputs (one stimulus every 20 s) by application of the metabotropic glutamate receptor (mGluR) agonist, aminocyclopentane-1S, 3R-dicarboxylic acid (ACPD). This effect was blocked and long-term potentiation (LTP) was induced by co-application of N-methyl-d-aspartate (NMDA) during ACPD perfusion (ACPD/NMDA-induced LTD). These results indicate that the state of NMDA receptor activation during ACPD perfusion determines whether LTP or LTD is induced in hippocampal CA1 neurons. Co-application of an inositol 1, 4, 5-trisphosphate (IP3) receptor inhibitor, 2-aminotheoxydiphenyl borate, during ACPD application had no effect on the ACPD/NMDA-induced LTP, but increased the magnitude of the ACPD-induced LTD, suggesting that the ACPD/NMDA-induced LTP involves NMDA receptors, but not IP3 receptors, whereas the converse applies to the ACPD-induced LTD. [Copyright &y& Elsevier]