DOI： 10.1002/npr2.12033

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DOI： 10.18632/oncotarget.18560

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Electroconvulsive therapy (ECT) is a highly effective and fast-acting treatment for depression. Despite a long history of clinical use, its mechanism of action remains poorly understood. Recently, a novel cellular mechanism of antidepressant action has been proposed: the phenotype of mature brain neurons is transformed to immature-like one by antidepressant drug treatments. We show here that electroconvulsive stimulation (ECS), an animal model of ECT, causes profound changes in maturation-related phenotypes of neurons in the hippocampal dentate gyrus of adult mice. Single ECS immediately reduced expression of mature neuronal markers in almost entire population of dentate granule cells. After ECS treatments, granule cells showed some of physiological properties characteristic of immature granule cells such as higher somatic intrinsic excitability and smaller frequency facilitation at the detate-to-CA3 synapse. The rapid downregulation of maturation markers was suppressed by antagonizing glutamate NMDA receptors, but not by perturbing the serotonergic system. While single ECS caused short-lasting effects, repeated ECS induced stable changes in the maturation-related phenotypes lasting more than 2 weeks along with enhancement of synaptic excitation of granule cells. Augmentation of synaptic inhibition or blockade of NMDA receptors after repeated ECS facilitated regaining the initial mature phenotype, suggesting a role for endogenous neuronal excitation in maintaining the altered maturation-related phenotype probably via NMDA receptor activation. These results suggest that brief neuronal activation by ECS induces "dematuration" of the mature granule cells and that enhanced endogenous excitability is likely to support maintenance of such a demature state. The global increase in neuronal excitability accompanying this process may be relevant to the high efficacy of ECT.

DOI： 10.1186/s13041-017-0288-9

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Electroconvulsive therapy (ECT) is an established effective treatment for medication-resistant depression with the rapid onset of action. However, its cellular mechanism of action has not been revealed. We have previously shown that chronic antidepressant drug treatments enhance dopamine D-1-like receptor-dependent synaptic potentiation at the hippocampal mossy fiber (MF)-CA3 excitatory synapse. In this study we show that ECT-like treatments in mice also have marked effects on the dopaminergic synaptic modulation. Repeated electroconvulsive stimulation (ECS), an animal model of ECT, strongly enhanced the dopamine-induced synaptic potentiation at the MF synapse in hippocampal slices. Significant enhancement was detectable after the second ECS, and further repetition of ECS up to 11 times monotonously increased the magnitude of enhancement. After repeated ECS, the dopamine-induced synaptic potentiation remained enhanced for more than 4 wk. These synaptic effects of ECS were accompanied by increased expression of the dopamine D-1 receptor gene. Our results demonstrate that robust neuronal activation by ECS induces rapid and long-lasting enhancement of dopamine-induced synaptic potentiation at the MF synapse, likely via increased expression of the D-1 receptor, at least in part. This rapid enhancement of dopamine-induced potentiation at the excitatory synapse may be relevant to the fast-acting antidepressant effect of ECT.
NEW & NOTEWORTHY We show that electroconvulsive therapy (ECT)-like stimulation greatly enhances synaptic potentiation induced by dopamine at the excitatory synapse formed by the hippocampal mossy fiber in mice. The effect of ECT-like stimulation on the dopaminergic modulation was rapidly induced, maintained for more than 4 wk after repeated treatments, and most likely mediated by increased expression of the dopamine D-1 receptor. These effects may be relevant to fast-acting strong antidepressant action of ECT.

DOI： 10.1152/jn.00740.2016

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Background: Chronic treatment with selective serotonin (5-HT) reuptake inhibitors (SSRIs) facilitates adult neurogenesis and reverses the state of maturation in mature granule cells (GCs) in the dentate gyrus (DG) of the hippocampus. Recent studies have suggested that the 5-HT4 receptor is involved in both effects. However, it is largely unknown how the 5-HT4 receptor mediates neurogenic effects in the DG and, how the neurogenic and dematuration effects of SSRIs interact with each other.
Results: We addressed these issues using 5-HT4 receptor knockout (5-HT4R KO) mice. Expression of the 5-HT4 receptor was detected in mature GCs but not in neuronal progenitors of the DG. We found that chronic treatment with the SSRI fluoxetine significantly increased cell proliferation and the number of doublecortin-positive cells in the DG of wild-type mice, but not in 5-HT4R KO mice. We then examined the correlation between the increased neurogenesis and the dematuration of GCs. As reported previously, reduced expression of calbindin in the DG, as an index of dematuration, by chronic fluoxetine treatment was observed in wild-type mice but not in 5-HT4R KO mice. The proliferative effect of fluoxetine was inversely correlated with the expression level of calbindin in the DG. The expression of neurogenic factors in the DG, such as brain derived neurotrophic factor (Bdnf), was also associated with the progression of dematuration. These results indicate that the neurogenic effects of fluoxetine in the DG are closely associated with the progression of dematuration of GCs. In contrast, the DG in which neurogenesis was impaired by irradiation still showed significant reduction of calbindin expression by chronic fluoxetine treatment, suggesting that dematuration of GCs by fluoxetine does not require adult neurogenesis in the DG.
Conclusions: We demonstrated that the 5-HT4 receptor plays an important role in fluoxetine-induced adult neurogenesis in the DG in addition to GC dematuration, and that these phenomena are closely associated. Our results suggest that 5-HT4 receptor-mediated phenotypic changes, including dematuration in mature GCs, underlie the neurogenic effect of SSRIs in the DG, providing new insight into the cellular mechanisms of the neurogenic actions of SSRIs in the hippocampus.

DOI： 10.1186/s13041-015-0120-3

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Background: Voltage-dependent block of the NMDA receptor by Mg2+ is thought to be central to the unique involvement of this receptor in higher brain functions. However, the in vivo role of the Mg2+ block in the mammalian brain has not yet been investigated, because brain-wide loss of the Mg2+ block causes perinatal lethality. In this study, we used a brain-region specific knock-in mouse expressing an NMDA receptor that is defective for the Mg2+ block in order to test its role in neural information processing.
Results: We devised a method to induce a single amino acid substitution (N595Q) in the GluN2A subunit of the NMDA receptor, specifically in the hippocampal dentate gyrus in mice. This mutation reduced the Mg2+ block at the medial perforant path-granule cell synapse and facilitated synaptic potentiation induced by high-frequency stimulation. The mutants had more stable hippocampal place fields in the CA1 than the controls did, and place representation showed lower sensitivity to visual differences. In addition, behavioral tests revealed that the mutants had a spatial working memory deficit.
Conclusions: These results suggest that the Mg2+ block in the dentate gyrus regulates hippocampal spatial information processing by attenuating activity-dependent synaptic potentiation in the dentate gyrus.

DOI： 10.1186/1756-6606-7-44

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Background: Loss of adenomatous polyposis coli (APC) gene function results in constitutive activation of the canonical Wnt pathway and represents the main initiating and rate-limiting event in colorectal tumorigenesis. APC is likely to participate in a wide spectrum of biological functions via its different functional domains and is abundantly expressed in the brain as well as in peripheral tissues. However, the neuronal function of APC is poorly understood. To investigate the functional role of Apc in the central nervous system, we analyzed the neurological phenotypes of Apc(1638T/1638T) mice, which carry a targeted deletion of the 3' terminal third of Apc that does not affect Wnt signaling.
Results: A series of behavioral tests revealed a working memory deficit, increased locomotor activity, reduced anxiety-related behavior, and mildly decreased social interaction in Apc(1638T/1638T) mice. Apc(1638T/1638T) mice showed abnormal morphology of the dendritic spines and impaired long-term potentiation of synaptic transmission in the hippocampal CA1 region. Moreover, Apc(1638T/1638T) mice showed abnormal dopamine and serotonin distribution in the brain. Some of these behavioral and neuronal phenotypes are related to symptoms and endophenotypes of schizophrenia.
Conclusions: Our results demonstrate that the C-terminus of the Apc tumor suppressor plays a critical role in cognitive and neuropsychiatric functioning. This finding suggests a potential functional link between the C-terminus of APC and pathologies of the central nervous system.

DOI： 10.1186/1756-6606-7-21

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Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia. © 2013 American College of Neuropsychopharmacology. All rights reserved.

DOI： 10.1038/npp.2013.38

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Objectives There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Methods Behaviors of calcium/calmodulin-dependent protein kinase II alpha (-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. Results The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal -CaMKII protein levels was also found in both models. Conclusions Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy and bipolar disorder/schizophrenia are strikingly similar.

DOI： 10.1111/bdi.12064

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The hippocampal dentate gyrus has been implicated in a neuronal basis of antidepressant action. We have recently shown a distinct form of neuronal plasticity induced by the serotonergic antidepressant fluoxetine, that is, a reversal of maturation of the dentate granule cells in adult mice. This "dematuration'' is induced in a large population of dentate neurons and maintained for at least one month after withdrawal of fluoxetine, suggesting long-lasting strong influence of dematuration on brain functioning. However, reliable induction of dematuration required doses of fluoxetine higher than suggested optimal doses for mice (10 to 18 mg/kg/day), which casts doubt on the clinical relevance of this effect. Since our previous studies were performed in naive mice, in the present study, we reexamined effects of fluoxetine using mice treated with chronic corticosterone that model neuroendocrine pathophysiology associated with depression. In corticosterone-treated mice, fluoxetine at 10 mg/kg/day downregulated expression of mature granule cell markers and attenuated strong frequency facilitation at the synapse formed by the granule cell axon mossy fiber, suggesting the induction of granule cell dematuration. In addition, fluoxetine caused marked enhancement of dopaminergic modulation at the mossy fiber synapse. In vehicle-treated mice, however, fluoxetine at this dose had no significant effects. The plasma level of fluoxetine was comparable to that in patients taking chronic fluoxetine, and corticosterone did not affect it. These results indicate that corticosterone facilitates fluoxetine-induced plastic changes in the dentate granule cells. Our finding may provide insight into neuronal mechanisms underlying enhanced responsiveness to antidepressant medication in certain pathological conditions.

DOI： 10.1371/journal.pone.0063662

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Background: Synaptosomal-associated protein, 25 kDa (SNAP-25) regulates the exocytosis of neurotransmitters. Growing evidence suggests that SNAP-25 is involved in neuropsychiatric disorders, such as schizophrenia, attention-deficit/hyperactivity disorder, and epilepsy. Recently, increases in anxiety-related behaviors and epilepsy have been observed in SNAP-25 knock-in (KI) mice, which have a single amino acid substitution of Ala for Ser187. However, the molecular and cellular mechanisms underlying the abnormalities in this mutant remain unknown.
Results: In this study, we found that a significant number of dentate gyrus (DG) granule cells was histologically and electrophysiologically similar to immature DG neurons in the dentate gyrus of the adult mutants, a phenomenon termed the "immature DG" (iDG). SNAP-25 KI mice and other mice possessing the iDG phenotype, i.e., alphacalcium/calmodulin-dependent protein kinase II heterozygous mice, Schnurri-2 knockout mice, and mice treated with the antidepressant fluoxetine, showed similar molecular expression patterns, with over 100 genes similarly altered. A working memory deficit was also identified in mutant mice during a spontaneous forced alternation task using a modified T-maze, a behavioral task known to be dependent on hippocampal function. Chronic treatments with the antiepileptic drug valproate abolished the iDG phenotype and the working memory deficit in mutants.
Conclusions: These findings suggest that the substitution of Ala for Ser187 in SNAP-25 induces the iDG phenotype, which can also be caused by epilepsy, and led to a severe working memory deficit. In addition, the iDG phenotype in adulthood is likely an endophenotype for at least a part of some common psychiatric disorders.

DOI： 10.1186/1756-6606-6-12

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Background: Postsynaptic density (PSD) 95-like membrane-associated guanylate kinases (PSD-MAGUKs) are scaffold proteins in PSDs that cluster signaling molecules near NMDA receptors. PSD-MAGUKs share a common domain structure, including three PDZ (PDZ1/2/3) domains in their N-terminus. While multiple domains enable the PSD-MAGUKs to bind various ligands, the contribution of each PDZ domain to synaptic organization and function is not fully understood. Here, we focused on the PDZ1/2 domains of PSD-95 that bind NMDA-type receptors, and studied the specific roles of the ligand binding of these domains in the assembly of PSD proteins, synaptic properties of hippocampal neurons, and behavior, using ligand binding-deficient PSD-95 cDNA knockin (KI) mice.
Results: The KI mice showed decreased accumulation of mutant PSD-95, PSD-93 and AMPA receptor subunits in the PSD fraction of the hippocampus. In the hippocampal CA1 region of young KI mice, basal synaptic efficacy was reduced and long-term potentiation (LTP) was enhanced with intact long-term depression. In adult KI mice, there was no significant change in the magnitude of LTP in CA1, but robustly enhanced LTP was induced at the medial perforant path-dentate gyrus synapses, suggesting that PSD-95 has an age-and subregion-dependent role. In a battery of behavioral tests, KI mice showed markedly abnormal anxiety-like behavior, impaired spatial reference and working memory, and impaired remote memory and pattern separation in fear conditioning test.
Conclusions: These findings reveal that PSD-95 including its ligand binding of the PDZ1/2 domains controls the synaptic clustering of PSD-MAGUKs and AMPA receptors, which may have an essential role in regulating hippocampal synaptic transmission, plasticity, and hippocampus-dependent behavior.

DOI： 10.1186/1756-6606-5-43

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The dentate gyrus of the hippocampus has been implicated in mechanisms of action of selective serotonin reuptake inhibitors (SSRIs). We have recently demonstrated that the SSRI fluoxetine can reverse the state of maturation of the adult dentate granule cells and enhances serotonin 5-HT4 receptor-mediated synaptic potentiation at the synapses formed by their mossy fiber axons. Here, we show that fluoxetine can induce long-lasting enhancement of dopaminergic modulation at the mossy fiber synapse. Synaptic responses arising from the mossy fiber-CA3 pyramidal cell synapse were recorded using acute mouse hippocampal slices. Dopamine potentiates mossy fiber synaptic transmission by activating D-1-like receptors. Chronic fluoxetine treatment induced a prominent increase in the magnitude of dopamine-induced synaptic potentiation, and this effect was maintained at least up to 1 month after withdrawal of fluoxetine. Quantitative autoradiography revealed that binding of the D-1-like receptor ligand [H-3]SCH23390 was selectively increased in the dentate gyrus and along the mossy fiber in fluoxetine-treated mice. However, binding of the 5-HT4 receptor ligand [H-3]GR113808 was not significantly changed. These results suggest that chronic fluoxetine enhanced the dopaminergic modulation at least in part by upregulating expression of D-1-like receptors, while the enhanced serotonergic modulation may be mediated by modifications of downstream signaling pathways. These enhanced monoaminergic modulations would greatly increase excitatory drive to the hippocampal circuit through the dentate gyrus. The highly localized upregulation of D-1-like receptors further supports the importance of the dentate gyrus in the mechanism of action of SSRIs. Neuropsychopharmacology (2012) 37, 1500-1508; doi: 10.1038/npp.2011.335; published online 25 January 2012

DOI： 10.1038/npp.2011.335

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Dysbindin-1 (dystrobrevin-binding protein 1, DTNBP1) is one of the promising schizophrenia susceptibility genes. Dysbindin protein is abundantly expressed in synaptic regions of the hippocampus, including the terminal field of the mossy fibers, and this hippocampal expression of dysbindin is strongly reduced in patients with schizophrenia. In the present study, we examined the functional role of dysbindin in hippocampal mossy fiber-CA3 synaptic transmission and its modulation using the sandy mouse, a spontaneous mutant with deletion in the dysbindin gene. Electrophysiological recordings were made in hippocampal slices prepared from adult male sandy mice and their wild-type littermates. Basic properties of the mossy fiber synaptic transmission in the mutant mice were generally normal except for slightly reduced frequency facilitation. Serotonin and dopamine, two major neuromodulators implicated in the pathophysiology of schizophrenia, can potentiate mossy fiber synaptic transmission probably via an increase in cAMP levels. Synaptic potentiation induced by serotonin and dopamine was very variable in magnitude in the mutant mice, with some mice showing prominent enhancement as compared with the wild-type mice. In addition, the magnitude of potentiation induced by these monoamines significantly correlated with each other in the mutant mice, indicating that a subpopulation of sandy mice has marked hypersensitivity to both serotonin and dopamine. While direct activation of the cAMP cascade by forskolin induced robust synaptic potentiation in both wildtype and mutant mice, this forskolin-induced potentaition correlated in magnitude with the serotonin-induced potentiation only in the mutant mice, suggesting a possible change in coupling of receptor activation to downstream signaling. These results suggest that the dysbindin deficiency could be an essential genetic factor that causes synaptic hypersensitivity to dopamine and serotonin. The altered monoaminergic modulation at the mossy fiber synapse could be a candidate pathophysiological basis for impairment of hippocampus-dependent brain functions in schizophrenia.

DOI： 10.1371/journal.pone.0018113

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Background: Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat mood and anxiety disorders. However, neuronal bases for both beneficial and adverse effects of SSRIs remain poorly understood. We have recently shown that the SSRI fluoxetine can reverse the state of maturation of hippocampal granule cells in adult mice. The granule cell "dematuration" is induced in a large population of granule cells, and greatly changes functional and physiological properties of these cells. Here we show that this unique form of neuronal plasticity is correlated with a distinct change in behavior of mice.
Results: We chronically treated adult male mice with fluoxetine, and examined its effect on several forms of behavior of mice. During fluoxetine treatments, mice showed a marked increase in day-to-day fluctuations of home cage activity levels that was characterized by occasional switching between hypoactivity and hyperactivity within a few days. This destabilized cage activity was accompanied by increased anxiety-related behaviors and could be observed up to 4 weeks after withdrawal from fluoxetine. As reported previously, the granule cell dematuration by fluoxetine includes a reduction of synaptic facilitation at the granule cell output, mossy fiber, synapse to the juvenile level. Mossy fiber synaptic facilitation examined electrophysiologically in acute hippocampal slices also remained suppressed after fluoxetine withdrawal and significantly correlated with the fluctuation of cage activity levels in individual mice. Furthermore, in mice lacking the 5-HT4 receptor, in which the granule cell dematuration has been shown to be attenuated, fluoxetine had no significant effect on the fluctuation of cage activity levels.
Conclusions: Our results demonstrate that the SSRI fluoxetine can induce marked day-to-day changes in activity levels of mice in the familiar environment, and that the dematuration of the hippocampal granule cells is closely associated with the expression of this destabilized behavior. Based on these results, we propose that the granule cell dematuration can be a potential cellular basis underlying switching-like changes in the behavioral state associated with SSRI treatments.

DOI： 10.1186/1756-6606-4-12

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Serotonergic antidepressant drugs have been commonly used to treat mood and anxiety disorders, and increasing evidence suggests potential use of these drugs beyond current antidepressant therapeutics. Facilitation of adult neurogenesis in the hippocampal dentate gyrus has been suggested to be a candidate mechanism of action of antidepressant drugs, but this mechanism may be only one of the broad effects of antidepressants. Here we show a distinct unique action of the serotonergic antidepressant fluoxetine in transforming the phenotype of mature dentate granule cells. Chronic treatments of adult mice with fluoxetine strongly reduced expression of the mature granule cell marker calbindin. The fluoxetine treatment induced active somatic membrane properties resembling immature granule cells and markedly reduced synaptic facilitation that characterizes the mature dentate-to-CA3 signal transmission. These changes cannot be explained simply by an increase in newly generated immature neurons, but best characterized as "dematuration" of mature granule cells. This granule cell dematuration developed along with increases in the efficacy of serotonin in 5-HT4 receptor-dependent neuromodulation and was attenuated in mice lacking the 5-HT4 receptor. Our results suggest that serotonergic antidepressants can reverse the established state of neuronal maturation in the adult hippocampus, and up-regulation of 5-HT4 receptor-mediated signaling may play a critical role in this distinct action of antidepressants. Such reversal of neuronal maturation could affect proper functioning of the mature hippocampal circuit, but may also cause some beneficial effects by reinstating neuronal functions that are lost during development.

DOI： 10.1073/pnas.0912690107

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Language：English   Publishing type：Part of collection (book)   Publisher：ELSEVIER ACADEMIC PRESS INC  

Signal transmission between the dentate gyrus and hippocampal CA3 region is mediated by the mossy fibers (MFs), the axons of dentate granule cells. The MF-CA3 synaptic transmission is regulated by various neurotransmitters and neuromodulators. Since single MF inputs activated in bursts can generate postsynaptic action potentials and play an instructive role in associative synaptic plasticity at CA3 recurrent excitatory synapses, modulations of this input are supposed to have a substantial impact on activity of the hippocampal neuronal network. Intrinsic properties of the MF synapse and its modulatory system can be changed by environment and experience. Some of these extrinsic influences on the MF synapse may be mediated by hormones. The modulatory system at the MF synapse could also be a potential target for pharmacological treatments of psychiatric disorders. Here I review some of characteristic properties of the MF synapse and its modulatory system. (C) 2010 Elsevier Inc.

DOI： 10.1016/S0083-6729(10)82004-7

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It is widely known that new neurons are continuously generated in the dentate gyrus of the hippocampus in the adult mammalian brain. This neurogenesis has been implicated in depression and antidepressant treatments. Recent evidence also suggests that the dentate gyrus is involved in the neuropathology and pathophysiology of schizophrenia and other related psychiatric disorders. Especially, abnormal neuronal development in the dentate gyrus may be a plausible risk factor for the diseases. The synapse made by the mossy fiber, the output fiber of the dentate gyrus, plays a critical role in regulating neuronal activity in its target CA3 area. The mossy fiber synapse is characterized by remarkable activity-dependent short-term synaptic plasticity that is established during the postnatal development and is supposed to be central to the functional role of the mossy fiber. Any defects, including developmental abnormalities, in the dentate gyrus and drugs acting on the dentate gyrus can modulate the mossy fiber-CA3 synaptic transmission, which may eventually affect hippocampal functions. In this paper, I review recent evidence for involvement of the dentate gyrus and mossy fiber synapse in psychiatric disorders and discuss potential importance of drugs targeting the mossy fiber synapse either directly or indirectly in the therapeutic treatments of psychiatric disorders.

DOI： 10.1007/s12035-008-8049-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

Selective serotonin reuptake inhibitors (SSRIs) have been used to treat various psychiatric disorders. Although the cellular mechanisms underlying amelioration of particular symptoms are mostly unknown, recent studies have shown critical importance of the dentate gyrus of the hippocampus in behavioral effects of SSRIs in rodents. Here, we show that serotonin potentiates synaptic transmission between mossy fibers, the sole output of the dentate granule cells, and CA3 pyramidal cells in mouse hippocampal slices. This potentiation is mediated by activation of 5-HT4 receptors and intracellular cAMP elevation. A chronic treatment of mice with fluoxetine, a widely used SSRI, bidirectionally modulates the 5-HT-induced potentiation: Fluoxetine enhances the potentiation induced by lower concentrations of serotonin, while attenuates that by the higher concentration, which represents stabilization of synaptic 5-HT action. In contrast to the chronic treatment, an acute application of fluoxetine in slices induces a leftward shift in the dose-response curve of the 5-HT-induced potentiation. Thus, acute and chronic fluoxetine treatments have distinct effects on the serotonergic modulation of the mossy fiber synaptic transmission. Exposure of mice to novel environments induces increases in locomotor activity and hippocampal extracellular 5-HT levels. In mice chronically treated with fluoxetine, the novelty-induced hyperactivity is reduced without significant alterations in home cage activity and motor skills. Our results suggest that the chronic fluoxetine treatment can stabilize the serotonergic modulation of the central synaptic transmission, which may contribute to attenuation of hyperactive behaviors.

DOI： 10.1523/JNEUROSCI.1656-08.2008

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Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.

DOI： 10.1186/1756-6606-1-6

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Dopamine has been implicated in various brain functions and the pathology of neurological diseases. In the hippocampus, dopamine has been shown to induce acute depression of synaptic transmission in the CA1 region, but it remains largely unknown how it works in the CA3 region. We here report that dopamine induces acute synaptic potentiation at the synapse formed by mossy fibers (MFs) on mouse hippocampal CA3 pyramidal cells, but not at converging associational/commissural synapses. Dopamine potentiated both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NNIDA) components of MF synaptic responses similarly in respect of the magnitude and time course. The dopamine-induced potentiation was intact in the presence of picrotoxin, required activation of D-1-like receptors and was apparently occluded by an activator of adenylate cyclase. The potentiation was accompanied by a decrease in magnitude of synaptic facilitation, suggesting the presynaptic site for the expression of the potentiation. The present study is the first demonstration of acute potentiation of hippocampal excitatory synaptic transmission by dopamine, which is most probably mediated by presynaptic D-1-like receptor-cAMP cascades. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuropharm.2006.08.026

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The hippocampus has long been implicated in memory formation. Although accumulating evidence suggests involvement of the hippocampus in other brain functions including locomotor regulation and emotional processes, cellular and synaptic bases underlying these functions remain largely unknown. We here report that environmental manipulations in mice unveiled the association of locomotor activity with the hippocampal mossy fibre (MF) synaptic transmission. Electrophysiological recordings of synaptic responses were made using hippocampal slices prepared from mice whose behaviour had been analysed. Environmental enrichment induced parallel decreases in open-field locomotor activity and MF synaptic facilitation. Facilitation induced by paired-pulse stimulation at relatively long intervals (>= 200 ms) was selectively reduced while the basal synaptic efficacy and high-frequency transmission were unaffected. Social isolation caused a change in behaviour in an elevated plus-maze, but neither the open-field activity nor the MF synaptic transmission was significantly altered. Effects of dopamine, a neurotransmitter essential for locomotor regulation, on the MF synapse were also examined using these mice. Environmental manipulations did not cause significant changes in potentiation of the MF synaptic transmission induced by dopamine. However, analysis of behavioural and electrophysiological results in individual subjects revealed that locomotor activity negatively correlates with magnitude of the dopamine-induced potentiation. These results suggest that the MF synapse plays important roles in the regulation of locomotor activity. We propose that the MF synapse can serve as the synaptic model for certain forms of locomotor regulation, with potential importance for investigation of the pathophysiology of psychiatric diseases using animal models.

DOI： 10.1111/j.1460-9568.2006.05079

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

In the CA3 region of the hippocampus, extensive recurrent associational/commissural (A/C) connections made by pyramidal cells may function as a network for associative memory storage and recall. We here report that long-term potentiation (LTP) at the A/C synapses can be induced by association of brief spike trains in mossy fibers (MFs) from the dentate gyrus and A/C fibers. This LTP not only required substantial overlap between spike trains in MFs and A/C fibers, but also depended on the temporal order of these spike trains in a manner not predicted by the well-known rule of spike timing-dependent plasticity and requiring activation of type 1 metabotropic glutamate receptors. Importantly, spike trains in a putative single MF input provided effective postsynaptic activity for the induction of LTP at A/C synapses. Thus, the timing of spike trains in individual MFs may code information that is crucial for the associative modification of CA3 recurrent synapses.

DOI： 10.1016/S0896-6273(03)00873-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

Transmission at the hippocampal mossy fibre (MF)-CA3 pyramidal cell synapse is characterized by prominent activity-dependent facilitation, which is thought to provide a wide dynamic range in hippocampal informational flow. At this synapse in mice the magnitude of paired-pulse facilitation and frequency-dependent facilitation markedly decreased with postnatal development from 3 weeks (3W) to 9 weeks (9W). Throughout this period the mean amplitude and variance of unitary EPSCs stayed constant. By altering extracellular Ca2+/Mg2+ concentrations the paired-pulse ratio could be changed to a similar extent as observed during development. However, this was accompanied by an over 30-fold change in EPSC amplitude, suggesting that the developmental change in facilitation ratio cannot simply be explained by a change in release probability. With paired-pulse stimulation the Ca2+ transients at MF terminals, monitored using mag-fura-5, showed a small facilitation, but its magnitude remained similar between 3W and 9W mice. Pharmacological tests using CNQX, adenosine, LY341495, H-7 or KN-62 suggested that neither presynaptic receptors (kainate, adenosine and metabotropic glutamate) nor protein kinases are responsible for the developmental change in facilitation. Nevertheless, loading the membrane-permeable form of BAPTA attenuated the paired-pulse facilitation in 3W mice to a much greater extent than in 9W mice, resulting in a marked reduction in age difference. These results suggest that the developmental decrease in the MF synaptic facilitation arises from a change associated with residual Ca2+, a decrease in residual Ca2+ itself or a change in Ca2+-binding sites involved in the facilitation. A developmental decline in facilitation ratio reduces the dynamic range of MF transmission, possibly contributing to the stabilization of hippocampal circuitry.

DOI： 10.1113/jphysiol.2003.045948

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：STOCKTON PRESS  

1 To investigate the effects of various chemical classes of antipsychotic drugs: haloperidol, thioridazine, pimozide and clozapine, on the G-protein-activated inwardly rectifying K+ (GIRK) channels, we carried out Xenopus oocyte functional assays with GIRK1 and GIRK2 mRNAs or GIRK1 and GIRK4 mRNas.
2 In oocytes co-injected with GIRK1 and GIRK2 mRNas, application of each of the various antipsychotic drugs immediately caused a reduction of inward currents through the basally active GIRK channels. These responses were not observed in the presence of 3 mM Ba2+, which blocks the GIRK channels. In addition, in uninjected oocytes, none of the drugs tested produced any significant current response. These results indicate that all the antipsychotic drugs tested inhibited the brain-type GIRK1/2 heteromultimeric channels. Furthermore, similar results were obtained in oocytes co-injected with GIRK1 and GIRK4 mRNAs, indicating that the antipsychotic drugs also inhibited the cardiac-type GIRK1/4 heteromultimeric channels.
3 All the drugs tested inhibited, in a concentration-dependent manner, both types of GIRK channels with varying degrees of potency and effectiveness at micromolar concentrations. Only pimozide caused slight inhibition of these channels at nanomolar concentrations,
4 We conclude that the various antipsychotic drugs acted as inhibitors at the brain-type and cardiac-type GIRK channels. Our results suggest that inhibition of both types of GIRK channels by these drugs underlies some of the side effects, in particular seizures and sinus tachycardia, observed in clinical practice.

DOI： 10.1038/sj.bjp.0703224

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

Doc2 alpha is a synaptic vesicle-associated Ca2+-binding protein. To study the role of Doc2 alpha in synaptic transmission and modulation, we generated homozygous null Doc2 alpha mutant mice. In the CA1 region of hippocampal slices in the mutant mice, excitatory synaptic responses evoked with prolonged 5 Hz stimulation showed a significantly larger frequency facilitation followed by a steeper depression than those in wild-type mice, whereas there was no difference in synaptic transmission at lower frequencies or in paired-pulse facilitation. These results suggest that Doc2 alpha regulates synaptic transmission when high Ca2+ concentrations in the presynaptic terminal are sustained. Furthermore, the mutant mice showed impairment in long-term potentiation and passive avoidance task. Thus, Doc2 alpha may regulate transmitter release during repetitive synaptic activation, thereby contributing to memory formation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

Long-term potentiation (LTP) and long-term depression (LTD) are induced presynaptically at the hippocampal mossy fibre-CA3 synapse. Activation of presynaptic metabotropic glutamate receptors (mGluRs) is necessary, but not sufficient for the LTD induction. Using mouse hippocampal slices, we attempted to identify additional presynaptic factors involved in the induction of mossy fibre LTD. Suppression of a rise in the presynaptic intracellular Ca2+ concentration ([Ca2+](i)) with a membrane-permeable Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM), reduced the magnitude of LTD, whereas an increase in Ca2+ influx induced LTD, suggesting that an elevation of presynaptic [Ca2+](i) is crucial for the LTD induction. A broad-spectrum protein kinase inhibitor, H-7, blocked LTD without affecting a presynaptic inhibition induced by an mGluR agonist. Furthermore, LTD was reduced by an inhibitor of calmodulin or Ca2+/calmodulin-dependent protein kinases. Thus, we conclude that mossy fibre LTD requires an increase in presynaptic [Ca2+](i) and subsequent activation of Ca2+/calmodulin-dependent protein kinases. Because mossy fibre LTP may also require a rise in presynaptic [Ca2+](i), bidirectional long-term plasticity at the mossy fibre synapse is likely to be regulated by presynaptic Ca2+-dependent processes.

DOI： 10.1046/j.1460-9568.1999.00578.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

From pharmacological studies, platelet-activating factor (PAF) has been proposed as a retrograde messenger for long-term potentiation (LTP) in the hippocampal CA1 region. We re-examined a possible contribution of PAF to LTP with a more specific approach using mice deficient in the PAF receptor. The PAF receptor-deficient mice exhibited normal LTP and showed no obvious abnormality in excitatory synaptic transmission. We also performed pharmacological experiments on the wild-type mice. Two structurally different antagonists of PAF receptors had no effects on LTP, Furthermore, the application of PAF itself caused no detectable changes in excitatory synaptic transmission. Thus, we conclude that the PAF receptor is not required for LTP in the CA1 region.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Nociceptin/orphanin FQ (N/OFQ) and its receptor share similarities to opioids and their receptors in terms of the molecular structure and signaling pathway, but the two systems exhibit different actions in vivo. To understand the mechanism of N/OFQ-system actions, we examined, by in situ hybridization analysis, the distribution of preproN/OFQ and N/OFQ receptor mRNAs in the developing and adult mouse central nervous systems (CNS). In most neural regions, preproN/OFQ mRNA was mainly expressed in a small population of middle-sized neurons. These neurons were scattered between large projection-type neurons or within the neuropil, suggestive of interneurons. In some other nuclei (lateral septum, bed nucleus of the stria terminalis, reticular thalamic nucleus, inferior colliculus, and rostral periolivery nucleus), preproN/OFQ mRNA was expressed in a number of large projection-type neurons. By contrast, N/OFQ receptor mRNA was evenly expressed in most neurons of the adult CNS. Considering the inhibitory actions of N/OFQ, the distinct cellular expression pattern of the N/OFQ system suggests that the release of N/OFQ from interneurons may lower neuronal and synaptic activities of neighboring neurons, leading to integration or modulation of local circuits. Furthermore, the cellular expression pattern, distinct from that of the opioid system, may provide a possible molecular/cellular basis for the different in vivo actions of N/OFQ and opioids. In embryonic stages, both preproN/OFQ and N/OFQ receptor mRNAs were highly and widely expressed in the mantle zone, suggesting the possible importance of N/OFQ signaling in CNS development. J. Comp. Neurol. 399:139-151, 1998. (C) 1998 Wiley-Liss, Inc.

DOI： 10.1002/(SICI)1096-9861(19980914)399:1<139::AID-CNE11>3.0.CO;2-C

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Nociceptin/orphanin FQ is a heptadecapeptide which was recently isolated from brains. It induces hyperalgesia, in contrast to the analgesic effects of opioid ligands, although it and its receptor structurally resemble opioid peptides and opioid receptors, respectively. To investigate the molecular mechanism underlying nociceptin/orphanin FQ actions, we performed Xenopus oocyte expression assays, in situ hybridization histochemistry and electrophysiological analyses of neurons. We found that the nociceptin/orphanin FQ receptor is functionally coupled with the G-protein-activated K+ (GIRK) channel in Xenopus oocytes, and that the receptor mRNA and GIRK1 mRNA co-exist in various neurons, including hippocampal pyramidal cells. Furthermore, we found that nociceptin/orphanin FQ induces hyperpolarizing currents via inward-rectifier K+ channels in hippocampal pyramidal cells, suggesting that the nociceptin/orphanin FQ receptor couples with the GIRK channel in this region. We conclude that the nociceptin/orphanin FQ receptor couples with the GIRK channel in various neurons, including hippocampal pyramidal cells, thereby modulating neuronal excitability.

DOI： 10.1016/S0169-328X(96)00252-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

Subtype 2 of the metabotropic glutamate receptor (mGluR2) is expressed in the presynaptic elements of hippocampal messy fiber-GAS synapses. Knockout mice deficient in mGluR2 showed no histological changes and no alterations in basal synaptic transmission, paired-pulse facilitation, or tetanus-induced long-term potentiation (LTP) al the messy fiber-CA3 synapses. Long-term depression (LTD) induced by low-frequency stimulation, however, was almost fully abolished. The mutant mice performed normally in water maze learning tasks. Thus, the presynaptic mGluR2 is essential for inducing LTD at the mossy fiber-CA3 synapses, but this hippocampal LTD does not seem to be required for spatial learning.

DOI： 10.1126/science.273.5275.645

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength may underlie learning and memory in the brain. The induction of LTP occurs in postsynaptic cells in the hippocampal CA1 region but is presynaptic in CA3. LTD is also well characterized in CA1 but not in CA3. Low-frequency stimulation of mouse hippocampal slices caused homosynaptic LTD at the messy fiber-CA3 synapse, which may be induced presynaptically by activation of metabotropic glutamate receptors. Thus, the efficacy of messy fiber-CA3 synapses can be regulated bidirectionally, which may contribute to neuronal information processing.

DOI： 10.1126/science.273.5275.648

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROCKEFELLER UNIV PRESS  

Synapsin I is one of the major synaptic vesicle-associated proteins. Previous experiments implicated its crucial role in synaptogenesis and transmitter release. To better define the role of synapsin I in vivo, we used gene targeting to disrupt the murine synapsin I gene. Mutant mice lacking synapsin I appeared to develop normally and did not have gross anatomical abnormalities. However, when we examined the presynaptic structure of the hippocampal CA3 field in detail, we found that the sizes of messy fiber giant terminals were significantly smaller, the number of synaptic vesicles became reduced, and the presynaptic structures altered, although the messy fiber long-term potentiation remained intact. These results suggest significant contribution of synapsin I to the formation and maintenance of the presynaptic structure.

DOI： 10.1083/jcb.131.6.1789

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

1. To investigate regulation of the intracellular free Ca2+ concentration ([Ca2+](i)) in presynaptic terminals, the Ca2+ current (I-Ca) and [Ca2+](i) in axon terminals were simultaneously monitored in acutely dissociated retinal bipolar cells under whole-cell voltage clamp.
2. The recovery phase of the Ca2+ transient, which was evoked by activation of I-Ca, became slower when the Na+-Ca2+ exchanger was suppressed by removing extracellular Na+.
3. Inhibition of the plasma membrane Ca2+ pump produced by raising extracellular pH to 8.4 increased the basal [Ca2+](i) and caused incomplete recovery from the Ca2+ transient. These effects were not observed in orthovanadate-loaded bipolar cells.
4. The Ca2+ transient was not significantly affected by ryanodine, caffeine, thapsigargin, Ruthenium Red or FCCP. Internal Ca2+ stores may not participate in shaping the Ca2+ transient.
5. The ratio of the peak amplitude of the Ca2+ transient to the total amount of Ca2+ influx became smaller as the size of the Ca2+ influx increased. This action was not affected by blockage of Ca2+ transporters in the plasma membrane, or by reduction of the rate of Ca2+ influx. The peak amplitude of the Ca2+ transient seemed to be determined by Ca2+ buffering substances with a positive co-operativity.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CAMBRIDGE UNIV PRESS  

1. To study a possible contribution of intracellular Ca2+ stores to the presynaptic Ca2+ regulation, the Ca2+ current (I-Ca) and the intracellular free Ca2+ concentration ([Ca2+](i)) were simultaneously monitored in isolated goldfish retinal bipolar cells using the whole-cell voltage clamp procedure and fura-2 fluorimetry.
2. The Ca2+ transient triggered by the activation of I-Ca was potentiated when [Ca2+](i) was increased by applying either a prepulse or a small steady depolarization. The potentiation seemed to be partly due to the release of Ca2+ from intracellular Ca2+ stores.
3. The intracellular Ca2+ release was reversibly inhibited by caffeine but was not affected by ryanodine, suggesting that Ca2+ is released through intracellular Ca2+ channels which differ from ryanodine receptor channels.
4. These results suggest that the intracellular Ca2+ release may contribute to the facilitation of transmitter release.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

The release of neurotransmitter is evoked by activation of the Ca current (I(Ca)) at presynaptic terminals. Though multiple types of I(Ca) have been reported in various cells, little is known about the properties of presynaptic I(Ca) in the vertebrate CNS. The aim of this article is to identify the type of I(Ca) involved in the release of neurotransmitter from retinal bipolar cells. Bipolar cells with a large axon terminal were isolated enzymatically from the goldfish retina, and studied by the following techniques: (1) recordings of I(Ca) in the whole-cell recording configuration, (2) visualization of intracellular free Ca2 + concentration ([Ca2+]i) with the Fura-2 imaging system, and (3) real-time electrophysiological bioassay of released excitatory amino acid transmitter by a voltage-clamped horizontal cell isolated from the catfish retina. The only I(Ca) found in bipolar cells was the high-voltage-activated, dihydropyridine-sensitive type. This result supports the recent study by Heidelberger and Matthews (1992). When I(Ca) was activated by a short depolarizing pulse, a rapid increase of [Ca2+]i was restricted to the axon terminal. A much slower and smaller increase of [Ca2+]i Was sometimes observed at the cell body, probably due to the diffusion of intracellular free Ca2+ from the axon terminal. The increase of [Ca2+]i was completely suppressed by nicardipine, suggesting that Ca2+ entered through dihydropyridine-sensitive Ca channels located mainly at the axon terminal. Activating I(Ca) of the bipolar cell evoked a transmitter-induced current in the excitatory amino acid probe (i.e., the catfish horizontal cell). Both currents were suppressed concomitantly by nifedipine but not by omega-conotoxin. We conclude that the activation of dihydropyridine-sensitive I(Ca) causes a localized increase of [Ca2+]i at the axon terminal of bipolar cells, and results in the release of neurotransmitter.

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Language：Japanese  

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J-GLOBAL

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Language：Japanese   Publisher：オーム社  

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