Biomedical subjects

Y Ikegaya

Publications and source records attributed to Y Ikegaya.

At least 19 recordsLinked to original sources

PubMed2006

Hippocampal CA1 synaptic plasticity as a gamma transfer function.

The capacity of activity-dependent synaptic modification is essential in processing and storing information, yet little is known about how synaptic plasticity alters the input-output conversion efficiency at the synapses. In the adult mouse hippocampus in vivo, we carefully compared the input-output relationship, in terms of presynaptic activity levels versus postsynaptic potentials, before and after the induction of synaptic plasticity and found that synaptic plasticity led synapses to respond more robustly to inputs, that is, synaptic gain was increased as a function of synaptic activity with an expansive, power-law nonlinearity, i.e. conforming to the so-called gamma curve. In extreme cases, long-term potentiation and depression coexist in the same synaptic pathway with long-term potentiation dominating over long-term depression at higher levels of presynaptic activity. These findings predict a novel function of synaptic plasticity, i.e. a contrast-enhancing filtering of neural information through a gamma correction-like process.

Animals↗

PubMed2004

Hepatocyte growth factor as an enhancer of nmda currents and synaptic plasticity in the hippocampus.

Hepatocyte growth factor (HGF) promotes the survival and migration of immature neurons, but its role in the mature brain has remained elusive. In the hippocampus of juvenile rats, we found that the HGF receptor c-Met was expressed in neurons. Furthermore, it was highly Tyr-phosphorylated, more so than in the liver under normal conditions, suggesting that the receptor is activated and that HGF may act continuously in the intact brain. Exogenously applied HGF enhanced synaptic long-term potentiation (LTP) in the CA1 region of hippocampus, but did not affect long-term depression. We further found that HGF augmented N-methyl-D-aspartate receptor-mediated currents in both slices and dissociated neurons. This augmentation is likely to underlie the enhancement of LTP. Considering that the expression of both HGF and c-Met are known to be induced by ischemic stimuli, this modulation would provide a novel understanding of a neuronal regulatory systems shared with pathogenic ischemic states.

Animals↗

PubMed2002

Regionally selective neurotoxicity of NMDA and colchicine is independent of hippocampal neural circuitry.

The mechanisms by which cerebral ischemia and several neurotoxins cause regionally selective damages to the hippocampal formation are largely unknown. The CA1-selective toxicity of N-methyl--aspartate (NMDA), the CA3-selective toxicity of kainate, and the dentate gyrus (DG)-selective toxicity of colchicine were observed in organotypic entorhino-hippocampal cultures. The selective neurotoxicity of NMDA and colchicine but not kainate was present in isolated tissue cultures of each hippocampal subregion, suggesting that the regional vulnerability is irrespective of the hippocampal trisynaptic pathway. Dispersed cultures of neurons prepared from Ammon's horn and the DG still exhibited a preference for susceptibility to NMDA and colchicine, respectively. Thus, the neurons per se appear to be inherently susceptible to specific toxins independently of their original loci, intrinsic neural circuits, vascular system, or other systemic factors.

Animals↗

PubMed2001

Cyclic nucleotide-mediated regulation of hippocampal mossy fiber development: a target-specific guidance.

The mossy fibers (MFs) arising from dentate granule cells project primarily onto a narrow segment of the proximal dendrites of hippocampal CA3 pyramidal cells. The mechanisms underlying this specific MF target selection are not fully understood. To investigate the cellular basis for development of the stereotyped MF trajectories, we have arranged the fascia dentata and hippocampal Ammon's horn tissues in diverse topographical patterns in organotypic explant coculture systems. Here we show that cyclic nucleotide signaling pathways regulate the MF pathfinding. When the dentate gyrus explants were ectopically placed facing the CA3 stratum oriens of hippocampal slices, MFs crossed the border between cocultures and reached their appropriate target area in the Ammon's horn, as assessed by membrane tracer labeling, Timm staining, electrophysiological recording of synaptic responses, and optical analyses using a voltage-sensitive dye. This lamina-specific MF innervation was disrupted by pharmacological blockade of cGMP pathway. Similar apposition of the dentate grafts near the CA1 region of host slices rarely resulted in MF ingrowth into the Ammon's horn. Under blockade of cAMP pathway, however, the MFs were capable of making allopatric synapses with CA1 neurons. These data were further supported by the pharmacological data obtained from granule cells dispersed over hippocampal slice cultures. Thus, our findings suggest that the stereotyped MF extension is mediated by at least two distinct factors, i.e., an attractant derived from the CA3 region and a repellent from the CA1 region. These factors may be regulated differently by cAMP and cGMP signaling pathways.

Adenylyl Cyclase Inhibitors↗

PubMed2001

Spatial performance correlates with long-term potentiation of the dentate gyrus but not of the CA1 region in rats with fimbria-fornix lesions.

Although hippocampal long-term potentiation (LTP) is generally assumed to be a cellular mechanism of learning and memory, there has not been definitive evidence for this hypothesis. In the present study, therefore, we addressed the possible relationship between spatial learning ability and LTP by using rats with bilateral fimbria-fornix lesions. The animals were tested for spatial performance in spontaneous alternation behaviors with further in vivo investigation of LTP. The behavioral parameters of spatial memory showed a significant correlation with LTP in the dentate gyrus, but we found no evidence for a linkage with LTP in the CA1 region. Thus, LTP in the dentate gyrus may be important for spatial cognitive ability.

Animals↗

PubMed2001

Neuroprotective effects of lipoxygenase inhibitors against ischemic injury in rat hippocampal slice cultures.

Using organotypic cultures of rat hippocampal slices, we investigated the possible involvement of arachidonate cascades in neuronal death following ischemic insult. Oxygen/glucose deprivation-induced neuronal damage was efficiently attenuated by various inhibitors of lipoxygenase, whereas cyclooxygenase inhibitors were less effective. Interestingly, 5- and 12-lipoxygenases are likely to separately mediate ischemic injury in the hippocampus. The present study will provide novel therapeutic targets for the development of neuroprotective agents.

Animals↗

PubMed2001

Aberrant synaptic transmission in the hippocampal CA3 region and cognitive deterioration in protein-repair enzyme-deficient mice.

L-aspartate is the amino-acid residue most susceptible to spontaneous isomerization. This denaturation causes an alteration in the biological activity of the protein and is regarded as an aging process of the protein. Protein L-isoaspartyl methyltransferase (PIMT) repairs this post-translational modification and thus is implicated in retarding the aging process of proteins. PIMT is highly expressed in the brain, and its deficiency results in progressive epilepsy after 4 weeks of age, with a fatal seizure in mice. Here we report the pathophysiological role of this repair system in the hippocampal slice of PIMT-deficient mice. The hippocampal mossy fiber-CA3 synapses of PIMT-deficient mice showed hyperexcitation that was repressed by a gamma-aminobutyric acid (GABA)A receptor agonist muscimol. In addition, the mossy fiber-CA3 synapses failed to show long-term potentiation or paired-pulse facilitation. No abnormality, however, was observed in Schaffer collateral-CA1 synapses or in perforant path-dentate gyrus synapses. Electron microscopic study revealed aberrant distribution of synaptic vesicles in the mossy fiber terminals and vacuolar degeneration at the axon hillock of dentate granule cells in PIMT-deficient mice. Furthermore, the PIMT-deficient mice showed impaired spatial memory in Morris water maze test and exhibited fewer anxiety-related behaviors in the elevated-plus test. These results suggest that the mossy fiber-CA3 system is vulnerable to aspartate isomerization and that the PIMT-mediated repair system is essential for maintenance of normal functions of the hippocampus.

Aging↗

PubMed2001

Withdrawal from chronic morphine administration causes prolonged enhancement of immobility in rat forced swimming test.

RATIONALE: Opiate-dependent subjects experience severe depression as one of the subjective symptoms during withdrawal. No experimental work, however, has focused on the ability of opiate-withdrawal to produce depression-like behavior in dependent animal. OBJECTIVES. We therefore investigated whether withdrawal from chronic morphine treatment affects immobility in forced swimming test in rats. METHODS: Morphine was administered in a dose escalation fashion using doses ranging from 20 to 140 mg/kg twice daily for 14 days, followed by 1-6 days of withdrawal, and their duration of immobility was assessed. RESULTS: After the last morphine treatment. an increase in immobility occurred late on day 3 and persisted to at least day 6 of withdrawal without any change in ambulatory activity. CONCLUSIONS: The results suggest that the morphine withdrawal resulted in prolonged enhancement of depression-like behavior in drug-dependent laboratory animals.

Animals↗

PubMed2001

Docosahexaenoic acid improves long-term potentiation attenuated by phospholipase A(2) inhibitor in rat hippocampal slices.

1. We investigated the possible involvement of phospholipase A(2) (PLA(2)) and its products in long-term potentiation (LTP) in the CA1 neurotransmission of rat hippocampal slices. 2. Inhibitors of Ca(2+)-independent PLA(2) (iPLA(2)) prevented the induction of LTP without affecting the maintenance phase of LTP whereas Ca(2+)-dependent PLA(2) inhibitors were virtually ineffective, which suggests a pivotal role of iPLA(2) in the initiation of LTP. 3. We then investigated the effect of docosahexaenoic acid (DHA) and arachidonic acid (AA) on BEL (bromoenol lactone, an iPLA(2)-inhibitor) -impaired LTP, and found that either DHA or AA abolished the effect of BEL. However, DHA did not restore BEL-attenuated LTP when applied after the tetanus. DHA per se affected neither the induction nor maintenance of LTP. Linoleic acid had no effects, either. 4. These results suggest that DHA is crucial for the induction of LTP and that endogenously released DHA during tetanus is sufficient to trigger the formation of LTP.

Animals↗

PubMed2001

Phospholipase A2 mediates ischemic injury in the hippocampus: a regional difference of neuronal vulnerability.

Although it is well known that the hippocampal CA1 subfield is highly vulnerable to ischemic injury, cellular mechanisms leading to this neuronal degeneration are not fully understood. Using organotypic cultures of rat hippocampal slices, we determined whether phospholipase A2 (PLA2) is activated in response to ischemic conditions (OGD; oxygen and glucose deprivation). The PLA2 activity in the pyramidal cell layer increased immediately following a 35-min exposure to OGD, which was likely to be mediated by selective activation of cytosolic Ca2+-dependent PLA2 subtype (cPLA2). This enhancement lasted for at least 24 h. Interestingly, no apparent increase was detected in the dentate gyrus. Twenty-four hours after the OGD exposure, neuronal death was detected mainly in the CA1 region of hippocampal slices. To examine whether the PLA2 activation is causally or protectively involved in the ischemic injury, we investigated the effect of pharmacological blockade of PLA2 on the OGD-induced neuronal death. The PLA2 inhibitor bromophenacyl bromide efficiently prevented the cell death in a concentration-dependent manner. Similar results were obtained for the selective cPLA2 inhibitor AACOCF3. However, the Ca2+-independent PLA2 inhibitor bromoenol lactone and the secretory PLA2 inhibitor LY311727 were virtually ineffective. These results suggest that cPLA2 plays a causative role in the neuronal death following OGD exposure. Thus, the present study may provide novel therapeutic targets for the development of neuroprotective agents.

Animals↗

PubMed2001

Transient upregulation of the glial glutamate transporter GLAST in response to fibroblast growth factor, insulin-like growth factor and epidermal growth factor in cultured astrocytes.

Although expression of the glial glutamate transporter GLAST is tightly regulated during development and under pathophysiological conditions, little is known about endogenous modulators of GLAST expression. Because growth factors are generally believed to regulate glial functions, we addressed their possible contribution to GLAST regulation in cultured rat astrocytes. Of the six growth factors tested (basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), insulin, platelet-derived growth factor, and hepatocyte growth factor), bFGF, IGF-1 and EGF enhanced [(3)H]glutamate transport activity in a concentration-dependent manner. These effects were accompanied by an increase in the V(max) value for transport activity and in GLAST protein and mRNA levels, which suggests that GLAST expression is transcriptionally regulated by the growth factors. Interestingly, the effects reached a peak after 36 hours of exposure to growth factors, and rapidly returned to baseline by 48 hours. A combination of IGF-1 with either bFGF or EGF showed an additive effect on the glutamate uptake activity, but a combination of bFGF and EGF did not. Pharmacological blockade of protein kinase C inhibited the effects of IGF-1 and EGF, but not bFGF. By contrast, genistein, an inhibitor of tyrosine kinases, blocked the effects of bFGF and EGF without affecting the effect of IGF-1. These results suggest that the growth factors activate different signaling pathways for GLAST upregulation. The present study may indicate a novel regulatory system of glial glutamate transporters.

Amino Acid Transport System X-AG↗

PubMed2001

Rapid and reversible changes in dendrite morphology and synaptic efficacy following NMDA receptor activation: implication for a cellular defense against excitotoxicity.

Postsynaptic neuronal dendrites undergo functional and morphological changes in response to pathologically excessive synaptic activation. Although rapid formation of segmental focal swelling (varicosity) is the most prominent hallmark in such excitotoxic injury, little is known about the pathophysiological function of these structural alterations. We used cultured rat hippocampal slices to evaluate the relationship between the formation of varicosities and subsequent neuronal death. Substantial numbers of segmental dendritic varicosities were observed all over the hippocampus within 5 minutes of exposure to 30 microM NMDA, although neuronal death was detected only in the CA1 region 24 hours after NMDA exposure. Sublethal NMDA concentrations (1-10 microM) induced reversible focal swelling in all hippocampal subregions. NMDA-induced neuronal death was prevented either by NMDA receptor antagonists or by the use of Ca(2+)-free medium, whereas varicosity formation was virtually independent of Ca(2+) influx. Rather, the Ca(2+)-free conditions per se produced dendritic focal swelling. Also, NMDA-induced varicosity formation was dependent on extracellular Na+ concentration. Thus, we believe that varicosity formation is not causally related to neuronal injury and that the two phenomena are separable and involve distinct mechanisms. Interestingly, dendrite swelling was accompanied by AMPA receptor internalization and a rapid, long-lasting depression in synaptic transmission. Moreover, low Na+ conditions or treatment with ethacrynic acid or proteinase inhibitors, which effectively prevent varicosity formation, aggravated NMDA-induced excitotoxicity, and eliminated the regional specificity of the toxicity. Therefore, the pathological changes in dendrite morphology and function may be associated with an early, self-protective response against excitotoxicity.

Animals↗

PubMed2001

Deterioration of spatial learning performances in lipopolysaccharide-treated mice.

It is well demonstrated that acute or chronic stress leads to reduction of learning ability. Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, induces profound physiological and behavioral changes, including fever, decrease in food motivation, and decrease in social behavior. These changes might be interpreted as an acute stress reaction to the LPS. In the present study, therefore, we investigated the effects of LPS (400-800 microg/kg, i.p.) on spatial learning performances using C57BL/6J male mice. In the Morris water-maze task, spatial learning performances were examined in six trials of training for two consecutive days. LPS-treated mice took a longer time to reach the hidden platform than control mice (F(1,60)=4.80801, P<0.05 at 600 microg/kg). In addition, injection of LPS decreased the percent of correct choices in the Y-maze test (P<0.05 at 800 microg/kg). LPS, however, did not alter the body weight, grip tone, motor activity or swimming speed. Taken together, these results indicate that LPS treatment specifically impaired spatial learning performances.

Animals↗

PubMed2000

Bidirectional actions of docosahexaenoic acid on hippocampal neurotransmissions in vivo.

Docosahexaenoic acid (DHA), a 22-carbon fatty acid with six double bonds, is one of the major polyunsaturated fatty acids in fish oils or in the mammalian central nervous system and is believed to be essential for neuronal plasticity and development. In the present study, we evaluated the effect of DHA on hippocampal neurotransmissions using anesthetized rats. Field excitatory postsynaptic potential (fEPSP) evoked by stimulation of the Schaffer collaterals was recorded from the CA1 stratum radiatum. Following intracerebroventricular injection of DHA 25 nmol, the fEPSP slope decreased gradually in 30 min and was eventually suppressed by about 30%. On the other hand, when fEPSP was evoked by stimulation of the perforant path was recorded in the molecular layer of the dentate gyrus, an increase in fEPSP slope occurred over a similar time course after DHA injection. These phenomena were independent of N-methyl-D-aspartate receptor activity. Linoleic acid, one of polyunsaturated fatty acids, was virtually ineffective. Furthermore, we investigated the effect of DHA on hippocampal synaptic plasticity. Although DHA did not alter the profile of paired-pulse facilitation, it inhibited the induction of long-term potentiation in the CA1 area but not in the dentate gyrus. Thus, DHA exerts regionally different effects on hippocampal neurotransmission and may be a good tool for clarifying physiological functions of the hippocampus.

Animals↗

PubMed2000

Pharmacological property of tributyltin in vivo and in vitro.

Tributyltin (TBT), an assumed endocrine-disrupting chemical, is widely known to show harmful effects in invertebrates including the dioecious snails. As for mammals, there are several reports concerning TBT toxicology, but few indications about general pharmacology of TBT. In the present study, we comprehensively examined the pharmacological effects of TBT both in vivo and in vitro. TBT (0.3 or 1.0 mg/kg) attenuated the small intestinal propulsive activity measured by the charcoal method in vivo, and caused concentration-dependent relaxation of isolated guinea-pig ileum in vitro (1.0x10(-8)-3.0x10(-6) M). TBT induced concentration-dependent relaxation of guinea-pig trachea, which was not inhibited by pre-treatment with a beta-adrenoceptor antagonist. TBT caused a concentration-dependent contraction of rat aortae, and also evoked endothelium-dependent relaxation in the presence of an alpha-adrenoceptor antagonist. The relaxation was inhibited by a muscarinic receptor antagonist. TBT reduced the electrically evoked, sympathetic contractile responses of rat vas deferens, which were slightly prevented by an alpha(2)-adrenoceptor antagonist. These results suggest that TBT possesses diverse pharmacological properties in mammalian organs.

Journal Article↗

PubMed2000

Cytotoxicity of tributyltin in rat hippocampal slice cultures.

The neurotoxic effects of tributyltin (TBT), an endocrine-disrupting chemical, were evaluated in organotypic slice cultures of immature rat hippocampus. Confocal microscopy study with propidium iodide showed that TBT induced severe neuronal death in a concentration- and time-dependent manner with CA3 > CA1 > dentate gyrus ranking of vulnerability of the hippocampal subfields. Dead or damaged neurons exhibited chromatin condensation, which is one of the morphological characteristics of apoptosis, as revealed by acridine orange staining. TBT neurotoxicity was alleviated by application of free radical scavengers or antioxidants, such as catalase, superoxide dismutase, Trolox and alpha-tocopherol but not by ascorbic acid or N-acetyl-L-cysteine, which suggests an involvement of free radicals, particularly reactive oxygen species. Neurons displayed a long-lasting increase in intracellular Ca2+ concentrations after TBT treatment. Although neither N-methyl-D-aspartate (NMDA) receptor inhibitors nor voltage-sensitive Ca2+ channel blockers protected hippocampal neurons against TBT neurotoxicity, non-NMDA receptor antagonist completely prevented TBT-induced neurodegeneration. These data suggest that TBT provokes apoptosis-like neuronal cell death, which might be mediated by intracellular Ca2+ elevation and free radical generation via non-NMDA receptor activation.

Acridine Orange↗

PubMed2000

Morphine augments excitatory synaptic transmission in the dentate gyrus through GABAergic disinhibition.

The present study investigated the effect of morphine on synaptic transmission and long-term potentiation (LTP) in the dentate gyrus using rat hippocampal slice preparations. Field excitatory postsynaptic potential (fEPSP) and population spike (PS), evoked by stimulation of the perforant path, were recorded from the dentate molecular layer and the stratum granulosum, respectively. Following application of 10 microM morphine, PS amplitude increased gradually in 10 min and was eventually potentiated by approximately 50%. The phenomenon showed a concentration-dependent manner and was completely canceled by naloxone, a mu opioid receptor antagonist. Furthermore, morphine-induced PS augmentation was not detected in disinhibited hippocampal slices, which suggests that the inhibitory input to the dentate granule cells was required for the facilitatory effect of morphine. Neither fEPSP nor tetanus-induced LTP of PS was altered by morphine application. The data support the hypothesis that mu opioid receptor activity modulates inhibitory recurrent circuits in the dentate gyrus and thereby, indirectly plays a regulatory role for hippocampal excitatory neurotransmission.

Animals↗

PubMed2000

Distance of target search of isolated rat hippocampal neuron is about 150 microm.

Although the survival of neuronal cells is highly dependent on neural connections with afferents or targets,(10,14,15) little is known about the survival of immature neurons that have not yet encountered the partners. Herein, using cultures of isolated hippocampal neurons of rat embryos, we have attempted to elucidate the contribution of neurite outgrowth to neuron survival and found that neurons died at a certain degree of neurite length with apoptotic characteristics in cases of no contact with other neurons. The threshold was 143.4microm, which was about five times as long as the cell body diameter. It was altered by depolarization or in the presence of basic fibroblast growth factor. Thus, neurons may be designed to kill themselves if they cannot find their targets after exploration within a particular area, the extent of which is variable due to cellular conditions.

Animals↗