[Show abstract][Hide abstract] ABSTRACT: Synaptic plasticity is believed to be a cellular mechanism for memory formation in the brain. It has been known that the metabotropic glutamate receptor (mGluR) is required for persistent forms of memory and induction of synaptic plasticity. Application of mGluR agonists induces synaptic plasticity in the absence of electrical conditioning stimulation, such as high or low frequency stimulation. The direction of the mGluR-induced synaptic plasticity, i.e., either long-term potentiation (LTP) or long-term-depression (LTD), is dependent on whether N-methyl-D-aspartate receptors (NMDARs) are co-activated with mGluRs. ATP has modulatory effects on neuronal functions and, in particular, there is increasing evidence that it plays a crucial role in synaptic plasticity. LTP can be induced by application of ATP, and this effect is inhibited by NMDAR antagonist. Although cooperative effects of NMDARs and mGluRs and of NMDARs and extracellular ATP in synaptic plasticity have been revealed, the effect of extracellular ATP on mGluR-induced synaptic plasticity is unknown. In this article, we summarize published data on mGluR- and ATP-induced synaptic plasticity, and present new data showing that extracellular ATP facilitates both the LTP and LTD induced by mGluR activation.
[Show abstract][Hide abstract] ABSTRACT: The axonal conduction of action potentials in the nervous system is generally considered to be a stable signal for the relaying of information, and its dysfunction is involved in impairment of cognitive function. Recent evidence suggests that the conduction properties and excitability of axons are more variable than traditionally thought. To investigate possible changes in the conduction of action potentials along axons in the central nervous system, we recorded action potentials from granule cells that were evoked and conducted antidromically along unmyelinated mossy fibers in the rat hippocampus. To evaluate changes in axons by eliminating any involvement of changes in the somata, two latency values were obtained by stimulating at two different positions and the latency difference between the action potentials was measured. A conditioning electrical stimulus of 20 pulses at 1 Hz increased the latency difference and this effect, which lasted for approximately 30 s, was inhibited by the application of an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor antagonist or a GluK1-containing kainate receptor antagonist, but not by an AMPA receptor-selective antagonist or an N-methyl-d-aspartate receptor antagonist. These results indicated that axonal conduction in mossy fibers is modulated in an activity-dependent manner through the activation of GluK1-containing kainate receptors. These dynamic changes in axonal conduction may contribute to the physiology and pathophysiology of the brain.
European Journal of Neuroscience 10/2014; 41(1). DOI:10.1111/ejn.12762 · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nicotinic and muscarinic ACh receptor agonists and acetylcholinesterase inhibitors (AChEIs) can enhance cognitive function. However, it is unknown whether a common signaling pathway is involved in the effect. Here, we show that in vivo administration of nicotine, AChEIs, and an m1 muscarinic (m1) agonist increase glutamate receptor, ionotropic, N-methyl D-aspartate 2B (GluN2B)-containing NMDA receptor (NR2B-NMDAR) responses, a necessary component in memory formation, in hippocampal CA1 pyramidal cells, and that coadministration of the m1 antagonist pirenzepine prevents the effect of cholinergic drugs. These observations suggest that the effect of nicotine is secondary to increased release of ACh via the activation of nicotinic ACh receptors (nAChRs) and involves m1 receptor activation through ACh. In vitro activation of m1 receptors causes the selective enhancement of NR2B-NMDAR responses in CA1 pyramidal cells, and in vivo exposure to cholinergic drugs occludes the in vitro effect. Furthermore, in vivo exposure to cholinergic drugs suppresses the potentiating effect of Src on NMDAR responses in vitro. These results suggest that exposure to cholinergic drugs maximally stimulates the m1/guanine nucleotide-binding protein subunit alpha q/PKC/proline-rich tyrosine kinase 2/Src signaling pathway for the potentiation of NMDAR responses in vivo, occluding the in vitro effects of m1 activation and Src. Thus, our results indicate not only that nAChRs, ACh, and m1 receptors are on the same pathway involving Src signaling but also that NR2B-NMDARs are a point of convergence of cholinergic and glutamatergic pathways involved in learning and memory.
Proceedings of the National Academy of Sciences 08/2014; 111(34). DOI:10.1073/pnas.1408805111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Plastic changes in white matter have received considerable attention in relation to normal cognitive function and learning. Oligodendrocytes and myelin, which constitute the white matter in the central nervous system, can respond to neuronal activity with prolonged depolarization of membrane potential and/or an increase in the intracellular Ca2+ concentration. Depolarization of oligodendrocytes increases the conduction velocity of an action potential along axons myelinated by the depolarized oligodendrocytes, indicating that white matter shows functional plasticity, as well as structural plasticity. However, the properties and mechanism of oligodendrocyte depolarization-induced functional plastic changes in white matter are largely unknown. Here, we investigated the functional plasticity of white matter in the hippocampus using mice with oligodendrocytes expressing channelrhodopsin-2. Using extracellular recordings of compound action potentials at the alveus of the hippocampus, we demonstrated that light-evoked depolarization of oligodendrocytes induced early- and late-onset facilitation of axonal conduction that was dependent on the magnitude of oligodendrocyte depolarization; the former lasted for approximately 10 min, whereas the latter continued for up to 3 h. Using whole-cell recordings from CA1 pyramidal cells and recordings of antidromic action potentials, we found that the early-onset short-lasting component included the synchronization of action potentials. Moreover, pharmacological analysis demonstrated that the activation of Ba2+-sensitive K+ channels was involved in early- and late-onset facilitation, whereas 4-aminopyridine-sensitive K+ channels were only involved in the early-onset component. These results demonstrate that oligodendrocyte depolarization induces short- and long-term functional plastic changes in the white matter of the hippocampus and plays active roles in brain functions. GLIA 2014
[Show abstract][Hide abstract] ABSTRACT: Astrocytes regulate the activity of neighboring neurons by releasing chemical transmitters, including ATP. Adenosine levels in the cerebrospinal fluid of mice that express a mutant human glial fibrillary acidic protein in astrocytes are slightly elevated compared to those in wild type mice and this might result from the observed increased release by mutant astrocytes of ATP, which can be used to produce adenosine. Using hippocampal slices from these mutant mice, we examined whether the increased endogenous adenosine levels in the hippocampus modulate the reversal of long-term potentiation (LTP), i.e. depotentiation (DP), in CA1 neurons. In hippocampal slices from wild type mice, a stable LTP was induced by tetanic stimulation consisting of 100 pulses at 100 Hz, and this was reversed by a train of low frequency stimulation (LFS) of 500 pulses at 1 Hz applied 30 min later. This induction of DP was inhibited by application of either 100 nM adenosine or 0.5 nM N6-cyclopentyladenosine, an adenosine A1 receptor agonist, during LFS, indicating that the increase in extracellular adenosine levels attenuated DP induction by acting on adenosine A1 receptors. In contrast, although a stable LTP was also induced in hippocampal slices from mutant mice, induction of DP was inhibited, but DP could be induced by application, during LFS, of 50 nM 8-cyclopentyltheophylline, an adenosine A1 receptor antagonist. These results suggest that a small increase in extracellular adenosine levels resulting from increased ATP release by astrocytes results in attenuation of DP in hippocampal CA1 neurons in the mutant mice.
Brain Research 08/2014; 1578(1). DOI:10.1016/j.brainres.2014.07.005 · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We studied the synaptic plasticity of hippocampal CA1 neurons and spatial learning behavior in gerbils that had been loaded with a transient cerebral ischemia caused by 5 min or 10 min occlusion of the bilateral carotid arteries. The stimulus threshold to elicit the field responses after a transient cerebral ischemia was not different from that in controls, but there was a significant decrease in the magnitude of synaptic responses, which might result from the observed loss of neurons. Long-term potentiation (LTP) and depotentiation after a 10 min cerebral ischemia expressed as a percentage of the pre-tetanus or pre-low frequency stimulation value were almost the same as those in controls, although the actual magnitude of the LTP and depotentiation was lower than in controls. Gerbils that were loaded with a 10 min cerebral ischemia showed impairment in a spatial learning test when this was started 10 days after the cerebral ischemia, but not when it was started 20 days after the same cerebral ischemia. These results suggest that the changes in electrophysiological properties of hippocampal CA1 neurons seen at 10 days after a 10 min cerebral ischemia contribute to the impairment of spatial learning of gerbils seen at this time, and that the extra-CA1 regions might be involved in the recovery of spatial learning seen at 20 days after cerebral ischemia.
Biomedical Research 04/2013; 34(2):75-85. DOI:10.2220/biomedres.34.75 · 1.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The inositol 1,4,5-trisphosphate receptor (IP3R) is known to release Ca2+ from intracellular stores, but the identity of the store site and the properties of the IP3R were previously unknown. We found that the IP3R is a Ca2+ channel
that acts as an IP3 binding protein and is localized on the endoplasmic reticulum. The IP3R has a variety of functions in different cell types, including neuronal cells. In this article, we review recent knowledge on the roles of IP3Rs in synaptic plasticity
at hippocampal synapses. In both CA3 and CA1 neurons, activation of IP3Rs during prior low or high frequency synaptic stimulation (LFS or HFS) determines the direction of the synaptic plasticity induced by subsequent LFS or HFS, and Ca2+ release from internal stores through
IP3Rs and activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) are both required for induction of depotentiation (DP) during the long-term potentiation-inducing LFS (CA1 neurons) or HFS (CA3 neurons). CaMKII may exert its effect through phosphorylation of
either N-methyl-D-aspartate receptors (NMDARs) on postsynaptic CA1 neurons or group 1 metabotropic glutamate receptors on postsynaptic CA3 neurons. At both synapses, Ca2+ entering through NMDA receptors and/or released from internal stores during a subsequent DP-inducing
LFS activates phosphatases, resulting in a decrease in synaptic transmission. At CA3 synapses, activation of IP3Rs during a preconditioning LFS results in dephosphorylation events that lead to failure of a subsequent HFS to induce long-term potentiation. Thus, previous synaptic
inputs affect certain types of synaptic plasticity induced by subsequent synaptic inputs in hippocampal neurons via activation of IP3Rs.
[Show abstract][Hide abstract] ABSTRACT: Gangliosides (sialic acid-containing glycosphingolipids) play important roles in many physiological functions, including synaptic plasticity in the hippocampus, which has been suggested as the basal cellular process of learning and memory in the brain. In the present study, long-term potentiation (LTP) and long-term depression (LTD) in CA1 hippocampal neurons and learning behavior were examined in mice treated with (D)-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol ((D)-PDMP), an inhibitor of ganglioside biosynthesis. Mice treated with (D)-PDMP, but not those treated with (L)-PDMP, showed impairment of LTP induction in hippocampal CA1 neurons without any significant change in LTD formation and also showed a failure of learning in the 4-pellet taking test. These results indicate that de novo synthesis of gangliosides in the brain is involved in synaptic plasticity of LTP in mouse hippocampal CA1 neurons and plays important roles in learning and memory.
Biomedical Research 11/2012; 33(5):265-71. DOI:10.2220/biomedres.33.265 · 1.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the role of inositol 1, 4, 5-trisphosphate receptors (IP3Rs), activated during preconditioning low-frequency afferent stimulation (LFS), in the subsequent induction of long-term potentiation (LTP) in CA3 neurons in hippocampal slices from mature guinea pigs. Induction of LTP in the field excitatory postsynaptic potential (EPSP) by the delivery of high-frequency stimulation (HFS, a tetanus of two trains of 100 pulses at 100Hz with a 10s interval) to mossy fiber-CA3 neuron synapses was suppressed when CA3 synapses were preconditioned by the LFS of 1000 pulses at 2Hz and this effect was inhibited when the LFS preconditioning was performed in the presence of an IP3R antagonist or a protein phosphatase inhibitor. Furthermore, activation of group 1 metabotropic glutamate receptors (mGluRs) during HFS canceled the effects of an IP3R antagonist given during preconditioning LFS on the subsequent LTP induction at mossy fiber-CA3 synapses. These results suggest that, in hippocampal mossy fiber-CA3 neuron synapses, activation of IP3Rs during a preconditioning LFS results in dephosphorylation events that lead to failure of the HFS to induce subsequent LTP.
Brain research 02/2012; 1449:15-23. DOI:10.1016/j.brainres.2012.02.025 · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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(2+) blocked the translocation under OGD conditions. These results show that DGKζ cytoplasmic translocation is triggered by activation of NMDAR with subsequent extracellular Ca(2+) 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] 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 100 Hz with a 10s interval) and was reversed (depotentiated) by a train of LFS of 1000 pulses at 2 Hz applied 60 min later. This depotentiation was triggered by activation of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) during HFS, which may increase the postsynaptic intracellular Ca(2+) 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.
Brain research 03/2011; 1387:19-28. DOI:10.1016/j.brainres.2011.02.088 · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Action potentials are the fundamental signals for relaying information from one region to another in the nervous system. Action potentials are propagated along axons without decrease of their amplitudes and are conducted with constant velocity depending on axonal diameter and myelin. It is considered that the modulation of fi ring patterns of action potentials in the neural circuit infl uences the information processing in the brain. We investigated the modulatory eff ects of glial cells on the fi ring pattern and the axonal conduction of action potentials using rat hippocampal slice preparation. In our previous study, we focused on interneuron / perineuronal glial cell pairs in CA1 region and reported that perineuronal glial cells could be classifi ed into two groups, one group belong astrocytes （perineuronal astrocytes） and the other group oligodendrocytes （perineuronal oligodendrocytes）, based on their membrane properties and immunohistochemical study. Direct depolarization of perineuronal astrocytes modulated the directly induced fi ring pattern of the interneuron, with initial facilitation and subsequent suppression. We also studied the oligodendrocytes in the alveus and examined their modulatory effects on the conduction of action potentials along axons of CA1 pyramidal cells. Direct repetitive depolarization of oligodendrocytes shortened the latencies of action potentials evoked by antidromic stimulation. These results indicate that glial cells infl uence the firing pattern and axonal conduction of action potentials, and that their effects involve both facilitation and suppression.
[Show abstract][Hide abstract] ABSTRACT: In the present study, mice lacking the type 1 inositol-1,4,5-trisphosphate receptor (IP(3)R) were used to study the role of type 1 IP(3)Rs 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 IP(3)Rs 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 Ca(2+) concentration ([Ca(2+)](i)) in CA1 pyramidal neurons using fluorometry, we found that the decay time of the transient increase in the [Ca(2+)](i) evoked by the HFS in mutant mice was significantly longer than that in wild-type mice, whereas the [Ca(2+)](i) at rest and the magnitude of the [Ca(2+)](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 IP(3)Rs reduces the PPI induced by PPS in the CA1 region. These results indicate that a lack of type 1 IP(3)Rs causes a slower decay of the transient [Ca(2+)](i) in CA1 pyramidal neurons and attenuates the activity of inhibitory interneurons, resulting in enhancement of LTP induction.
Neuroscience Research 03/2010; 67(2):149-55. DOI:10.1016/j.neures.2010.03.002 · 1.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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-alpha7 nAChRs. We found that, in addition to alpha2 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-alpha7 nAChRs increased intracellular Ca(2+) levels at least in part via Ca(2+) 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 Ca(2+) chelator blocked LTP induction, suggesting the requirement of Ca(2+) signal for LTP induction. The induction of LTP was still observed in the presence of ryanodine, which inhibits Ca(2+) -induced Ca(2+) release from ryanodine-sensitive intracellular stores, and the L-type Ca(2+) channel blocker nifedipine. These results suggest that Ca(2+) entry through non-alpha7 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-alpha7 nAChRs.
European Journal of Neuroscience 02/2010; 31(3):463-76. DOI:10.1111/j.1460-9568.2009.07058.x · 3.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
The Neuroscientist 06/2009; 16(1):11-8. DOI:10.1177/1073858409334425 · 6.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rapid activation of nicotinic acetylcholine receptors (nAChRs) at various anatomical and cellular locations in the hippocampus differentially modulates the operation of hippocampal circuits. However, it is largely unknown how the continued presence of nicotine affects the normal operation of hippocampal circuits. Here, we used single and dual whole-cell recordings to address this question. We found that horizontally oriented interneurons in the stratum oriens/alveus continuously discharged action potentials in the presence of nicotine. In these interneurons, bath application of nicotine produced slow inward currents that were well maintained and inhibited by the non-alpha 7 antagonist dihydro-beta-erythroidine. Single-cell reverse transcription-polymerase chain reaction analysis showed that nicotine-responding interneurons were consistently positive for the alpha2 subunit mRNA. These observations suggest that in the presence of nicotine, a subset of interneurons in the stratum oriens/alveus are continuously excited due to the sustained activation of alpha2* nAChRs. These interneurons were synaptically connected to pyramidal cells, and nicotine increased inhibitory baseline currents at the synapses and suppressed phasic inhibition at the same synapses. Nicotine-induced inhibitory activity increased background noise and masked small phasic inhibition in pyramidal cells, originating from other interneurons in the stratum radiatum. Thus, the continued presence of nicotine alters the normal operation of hippocampal circuits by gating inhibitory circuits through activating a non-desensitizing alpha2 nAChR subtype on a distinct population of interneurons.
European Journal of Neuroscience 05/2009; 29(8):1588-603. DOI:10.1111/j.1460-9568.2009.06706.x · 3.18 Impact Factor