Hiroki Yasuda - Academia.edu (original) (raw)

Papers by Hiroki Yasuda

Research paper thumbnail of Electrophysiological Technique for Analysis of Synaptic Function of PKN1 in Hippocampus

Research paper thumbnail of S1-4 Roles of calcium and calcium/calmodulin-dependent phosphatase in the induction of long-term potentiation/depression in visual cortical slices of rats

Neuroscience Research Supplements, 1993

Research paper thumbnail of Lateral distribution of hypothalamic signals controlling thermoregulatory vasomotor activity and shivering in rats

The American journal of physiology

The present study explored the laterality of central nervous thermoregulatory control in anesthet... more The present study explored the laterality of central nervous thermoregulatory control in anesthetized rats by measuring paw skin vasomotor activity and cold-induced shivering in hind leg muscles during unilateral preoptic area and anterior hypothalamus (POAH) warming and electrical stimulation or during unilateral thermal stimulation of abdominal skin. Unilateral POAH warming produced vasodilation on both sides of the body, but vasodilation on the ipsilateral side always either occurred at a lower threshold hypothalamic temperature or was stronger than on the contralateral side. In a cold environment (5 degrees C), shivering was suppressed simultaneously in both hind legs when one side of the POAH was warmed, and shivering reappeared simultaneously on both sides when POAH warming stopped. These results suggest that different thermoregulatory effectors are regulated in a different way by each side of the POAH. Unilateral thermal stimulation of the abdominal skin, on the other hand, a...

Research paper thumbnail of Modes of action of local hypothalamic and skin thermal stimulation on salivary secretion in rats

The Journal of Physiology, 1990

In urethane or ketamine-anaesthetized rats, salivary secretion was observed when local brain site... more In urethane or ketamine-anaesthetized rats, salivary secretion was observed when local brain sites or trunk skin were stimulated thermally or electrically.

Research paper thumbnail of Ipsilateral hypothalamic control of thermally induced salivary secretion in rats

Neuroscience Research Supplements, 1989

Research paper thumbnail of Salivary secretion and grooming behaviour during heat exposure in freely moving rats

The Journal of Physiology, 1991

1. At neutral (24°C) and at hot (40°C) ambient temperatures (TR) salivary secretion from the subm... more 1. At neutral (24°C) and at hot (40°C) ambient temperatures (TR) salivary secretion from the submandibular gland of freely moving rats was recorded, together with simultaneous observation of saliva-spreading behaviour (grooming).

Research paper thumbnail of A switching role of postsynaptic calcium in the induction of long-term potentiation or long-term depression in visual cortex

Seminars in Neuroscience, 1996

Long-term potentiation (LTP) and depression (LTD) are considered to be an initial step in process... more Long-term potentiation (LTP) and depression (LTD) are considered to be an initial step in processes governing experience-dependent changes in neuronal function in cerebral neocortex. As a mechanism for the induction of LTP and LTD, it is hypothesized that an input-associated rise of Ca 2 + beyond a certain threshold at postsynaptic sites leads to LTP while a lower rise below the threshold leads to LTD. To test this Ca 2 + -switching hypothesis, the method of microscopic fluorometry with Ca 2 + indicators such as fura-2 has been employed. In this review, problems with this fura-2 method are described, and results obtained with other indicators having weaker Ca 2 + -chelating action are mentioned briefly.

Research paper thumbnail of Brain-Derived Neurotrophic Factor Prevents Low-Frequency Inputs from Inducing Long-Term Depression in the Developing Visual Cortex

The Journal of Neuroscience, Mar 15, 1999

Brain-derived neurotrophic factor (BDNF) is reported to enhance synaptic transmission and to play... more Brain-derived neurotrophic factor (BDNF) is reported to enhance synaptic transmission and to play a role in long-term potentiation in hippocampus and neocortex. If so, a shortage or blockade of BDNF might lead to another form of synaptic plasticity, long-term depression (LTD). To test this possibility and to elucidate mechanisms if it is the case, EPSCs evoked by test stimulation of layer IV were recorded from layer II/III neurons in visual cortical slices of young rats in the whole-cell voltage-clamp mode. LTD was induced by low-frequency stimulation (LFS) at 1 Hz for 10-15 min if each pulse of the LFS was paired with depolarization of neurons to Ϫ30 mV but was not induced if their membrane potentials were kept at Ϫ70 mV. Such an LTD was blocked by exogenously applied BDNF, probably through presynaptic mechanisms. Suppression of endogenous BDNF activity by the anti-BDNF antibody or an inhibitor for BDNF receptors made otherwise ineffective stimuli (LFS without postsynaptic depolarization) effective for LTD induction, suggesting that endogenous BDNF may prevent low-frequency inputs from inducing LTD in the developing visual cortex.

Research paper thumbnail of An increase in calcium through NMDA receptors in apical dendrites of layer II/III neurons of rat visual cortex

Research paper thumbnail of S3-2 Simultaneous measurements of synaptic input-induced calcium rise and changes in synaptic efficacy in cortical neurons loaded with a low-affinity Ca 2+ indicator

Neurosci Res, 1996

To test the hypothesis that long-term potentiation (LTP) is induced if an increase in Gas+ concen... more To test the hypothesis that long-term potentiation (LTP) is induced if an increase in Gas+ concentration at postsynaptic sites during tetanic synaptic inputs is higher than the certain threshold, while long-term depression (LTD) is induced if it is below the threshold, one can use microscopic fluorometry with a fluorescent Ca2+ indicator. Since high-affinity Ca2+ indicators such as fura-may interfere with physiological processes for the induction of LTP or LTD, we used another indicator, rhod-2 which has a much weaker chelating action than fura-2. Initially, rhodG/AM (membrane-permeable type) was applied to visual cortical slices of young rats. Field responses to test stimulation of layer IV of the cortex were recorded from layer ll/lll. Fluorescent signal of rhod-2 was detected through a window (50 x 50 urn) placed near the recording electrode in layer ll/lll. In slices in which LTP of field responses was induced by tetanic stimulation of layer IV, tetanus-induced rise in fluorescent signal was significantly larger than that in LTD-induced slices. Next, we injected rhod-2 directly into pyramidal-cell like neurons of layer ll/lll through a patch pipette from which excitatory postsynaptic potentials (EPSPs) were recorded. During tetanic stimulation, we often observed a marked increase in fluorescence intensity at apical dendritic areas about 50 urn distal from the soma. In neurons in which LTP of EPSPs was induced, the fluorescent increase at this area was significantly larger than that in neurons in which LTD was observed. These results seem to be consistent with the above-mentioned hypothesis.

Research paper thumbnail of 309 An increase in calcium through NMDA receptors in apical dendrites of layer II/III neurons of rat visual cortex

Neurosci Res, 1997

The possibility that NMDA receptors participate in input-induced Ca2+ rise at postsynaptic sites ... more The possibility that NMDA receptors participate in input-induced Ca2+ rise at postsynaptic sites was tested with whole-cell patch-clamp recording and fluorescent Ca2+ imaging in layer II/III pyramidal neurons of rat visual cortex . In the current-clamp mode, high-frequency stimulation of layer IV induced a prominent rise in fluorescence at apical dendritic sites 30-120um from the soma. Such a rise was reduced by a NMDA receptor antagonist, APV, by about 40% in 9 of 15 neurons. In Mg2+ -free medium the local Ca2+ rise in dendrites was induced by synaptic inputs in neurons which were clamped at -8OmV, and this rise was blocked by APV. A local fluorescence rise was also detected in neurons clamped at +lOmV, at which voltage-dependent Ca2+ channels should not be activated by synaptic inputs. This rise was blocked by APV. These results suggest that NMDA receptors contribute to the local Ca2+ rise induced by synaptic inputs in apical dendrites of layer II/III neurons in the cortex.

Research paper thumbnail of S1-4 Roles of calcium and calcium/calmodulin-dependent phosphatase in the induction of long-term potentiation/depression in visual cortical slices of rats

Neuroscience Research Supplements, 1993

Research paper thumbnail of Long-term depression in rat visual cortex is associated with a lower rise of postsynaptic calcium than long-term potentiation

Neuroscience Research, 1996

To test the hypothesis that an input-associated rise of Ca2+ at postsynaptic sites beyond a certa... more To test the hypothesis that an input-associated rise of Ca2+ at postsynaptic sites beyond a certain threshold leads to the induction of long-term potentiation (LTP) while a lower rise below the threshold leads to long-term depression (LTD), the method of microscopic Ca2+ fluorometry was employed simultaneously with recordings of synaptic activity from layer II/III of visual cortical slices prepared from young rats. The conventional Ca2+ indicators, such as fura-2 or fluo-3, may interfere with intracellular processes for the induction of LTP/LTD because of their strong Ca(2+)-chelating action. To minimize such a problem, another Ca2+ indicator, rhod-2, was used since it has a much weaker Ca(2+)-chelating action than those indicators. In 16 slices loaded with rhod-2 through the perfusion medium, tetanic stimulation of theta-burst type was applied to layer IV of the cortex and changes in Ca2+ concentration were analyzed in layer II/III from which field potentials to test stimulation of layer IV were recorded simultaneously. In 7 slices in which weak tetanic stimulation consisting of 0.1 ms duration pulses was applied to layer IV, LTD of field responses was induced, while LTP was induced in 6 of the 9 slices in which strong tetanus consisting of 0.2 ms pulses was applied. In the 6 slices in which LTP was induced, the peak rise of fluorescence intensity during tetanus was 13.9 +/- 0.2 (S.E.M.) %, which was significantly (t-test, P < 0.01) higher than that (10.4 +/- 0.3%) in the 9 slices in which LTD was induced. In another series of experiments, rhod-2 was injected directly into 12 pyramidal cell-like neurons in layer II/III through patch pipettes, and changes in Ca2+ concentration in apical dendritic areas during tetanus were measured simultaneously with recordings of excitatory postsynaptic potentials (EPSPs) evoked by test stimulation of layer IV. It was found that LTP of EPSPs was induced in 4 cells which exhibited a strong rise of dendritic Ca2+ signal (197.1 +/- 18.5%) while LTD was induced in other 5 cells which showed a weak rise of the signal (31.0 +/- 4.1%). These results seem consistent with the above-mentioned, Ca(2+)-switching hypothesis for the induction of LTP and LTD in visual cortex.

Research paper thumbnail of Turning on of CICR in LTD induction after critical period of NR2 subunits switch

Neuroscience Research, 2011

Abstracts / Neuroscience Research 71S (2011) e108-e415 e219 found that the relationship was enhan... more Abstracts / Neuroscience Research 71S (2011) e108-e415 e219 found that the relationship was enhanced in SDRs, indicating that the efficacy of basal synaptic transmission was increased. Western blot analysis showed that there was no significant difference in the expression of GluA1, GluA2, PSD95 and presynaptic proteins between SDRs and control rats. However, the expression of NMDAR subunits, GluN1, GluN2A and GluN2B, was increased in the CA1 region of SDRs. Correspondingly, SDRs showed an increase in the ratio of NMDAR-to AMPAR-mediated synaptic currents in whole-cell patchclamp recordings from CA1 pyramidal cells. Furthermore, SDRs exhibited enhanced LTP induced by tetanic stimulation, as expected from the increased NMDAR expression. Taken together, our results suggest that GH regulates the expression of NMDA receptors in the hippocampus, which may result in modification of abilities of learning and memory in the whole animal.

Research paper thumbnail of S3-2 Simultaneous measurements of synaptic input-induced calcium rise and changes in synaptic efficacy in cortical neurons loaded with a low-affinity Ca2+ indicator

Neuroscience Research, 1996

To test the hypothesis that long-term potentiation (LTP) is induced if an increase in Gas+ concen... more To test the hypothesis that long-term potentiation (LTP) is induced if an increase in Gas+ concentration at postsynaptic sites during tetanic synaptic inputs is higher than the certain threshold, while long-term depression (LTD) is induced if it is below the threshold, one can use microscopic fluorometry with a fluorescent Ca2+ indicator. Since high-affinity Ca2+ indicators such as fura-may interfere with physiological processes for the induction of LTP or LTD, we used another indicator, rhod-2 which has a much weaker chelating action than fura-2. Initially, rhodG/AM (membrane-permeable type) was applied to visual cortical slices of young rats. Field responses to test stimulation of layer IV of the cortex were recorded from layer ll/lll. Fluorescent signal of rhod-2 was detected through a window (50 x 50 urn) placed near the recording electrode in layer ll/lll. In slices in which LTP of field responses was induced by tetanic stimulation of layer IV, tetanus-induced rise in fluorescent signal was significantly larger than that in LTD-induced slices. Next, we injected rhod-2 directly into pyramidal-cell like neurons of layer ll/lll through a patch pipette from which excitatory postsynaptic potentials (EPSPs) were recorded. During tetanic stimulation, we often observed a marked increase in fluorescence intensity at apical dendritic areas about 50 urn distal from the soma. In neurons in which LTP of EPSPs was induced, the fluorescent increase at this area was significantly larger than that in neurons in which LTD was observed. These results seem to be consistent with the above-mentioned hypothesis.

Research paper thumbnail of 309 An increase in calcium through NMDA receptors in apical dendrites of layer II/III neurons of rat visual cortex

Neuroscience Research, 1997

The possibility that NMDA receptors participate in input-induced Ca2+ rise at postsynaptic sites ... more The possibility that NMDA receptors participate in input-induced Ca2+ rise at postsynaptic sites was tested with whole-cell patch-clamp recording and fluorescent Ca2+ imaging in layer II/III pyramidal neurons of rat visual cortex . In the current-clamp mode, high-frequency stimulation of layer IV induced a prominent rise in fluorescence at apical dendritic sites 30-120um from the soma. Such a rise was reduced by a NMDA receptor antagonist, APV, by about 40% in 9 of 15 neurons. In Mg2+ -free medium the local Ca2+ rise in dendrites was induced by synaptic inputs in neurons which were clamped at -8OmV, and this rise was blocked by APV. A local fluorescence rise was also detected in neurons clamped at +lOmV, at which voltage-dependent Ca2+ channels should not be activated by synaptic inputs. This rise was blocked by APV. These results suggest that NMDA receptors contribute to the local Ca2+ rise induced by synaptic inputs in apical dendrites of layer II/III neurons in the cortex.

Research paper thumbnail of Imaging of calcineurin activated by long-term depression-inducing synaptic inputs in living neurons of rat visual cortex

European Journal of Neuroscience, 2003

Long-term depression (LTD) of synaptic transmission is induced by low-frequency stimulation (LFS)... more Long-term depression (LTD) of synaptic transmission is induced by low-frequency stimulation (LFS) of afferents lasting for a long time, typically for 10±15 min, in neocortical and hippocampal slices. It is suggested that calcineurin, Ca 2 /calmodulin-dependent protein phosphatase, plays a role in the induction of LTD, based on the results that pharmacological or genetic manipulation of calcineurin activity interfered in its induction. However, questions as to why it takes so long to induce LTD and in which compartment of neurons calcineurin is activated remain unanswered. With a¯uorescent indicator for calcineurin activity, we visualized the spatiotemporal pattern of its activation in living neurons in layer II/III of visual cortical slices of rats during the LFS of layer IV that induced LTD of synaptic responses. During LFS, the¯uorescence intensity gradually increased with a latency of a few minutes in dendrites and soma of neurons, and remained increased during the whole observation period (10±25 min) after LFS. The onset latency of the increase in the soma was slower than that in the distal dendritic region. The LFS-induced rise in¯uorescence was not observed in neurons which were loaded with inhibitors of calcineurin, indicating that the intensity of¯uorescence re¯ects calcineurin activity. Control stimulation at 0.05 Hz and y-burst stimulation did not signi®cantly change the intensity of¯uorescence. Only LFS-type inputs effectively activate calcineurin in postsynaptic neurons in an augmenting manner, and such a time-consuming activation of calcineurin may be a reason why long-lasting LFS is necessary for the induction of LTD.

Research paper thumbnail of PSD-Zip70 Deficiency Causes Prefrontal Hypofunction Associated with Glutamatergic Synapse Maturation Defects by Dysregulation of Rap2 Activity

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 21, 2015

Dysregulation of synapse formation and plasticity is closely related to the pathophysiology of ps... more Dysregulation of synapse formation and plasticity is closely related to the pathophysiology of psychiatric and neurodevelopmental disorders. The prefrontal cortex (PFC) is particularly important for executive functions such as working memory, cognition, and emotional control, which are impaired in the disorders. PSD-Zip70 (Lzts1/FEZ1) is a postsynaptic density (PSD) protein predominantly expressed in the frontal cortex, olfactory bulb, striatum, and hippocampus. Here we found that PSD-Zip70 knock-out (PSD-Zip70KO) mice exhibit working memory and cognitive defects, and enhanced anxiety-like behaviors. These abnormal behaviors are caused by impaired glutamatergic synapse transmission accompanied by tiny-headed immature dendritic spines in the PFC, due to aberrant Rap2 activation, which has roles in synapse formation and plasticity. PSD-Zip70 modulates the Rap2 activity by interacting with SPAR (spine-associated RapGAP) and PDZ-GEF1 (RapGEF) in the postsynapse. Furthermore, suppression...

Research paper thumbnail of Regulation of excitability and plasticity by endocannabinoids and PKA in developing hippocampus

Proceedings of the National Academy of Sciences of the United States of America, Jan 26, 2008

The activity-dependent strengthening and weakening of synaptic transmission are hypothesized to b... more The activity-dependent strengthening and weakening of synaptic transmission are hypothesized to be the basis of not only memory and learning but also the refinement of neural circuits during development. Here we report that, in the developing CA1 area of the hippocampus, endocannabinoid (eCB)-mediated heterosynaptic long-term depression (LTD) of glutamatergic excitatory synaptic transmission is associated with PKA-mediated homosynaptic long-term potentiation (LTP). This form of LTD was dominant at postnatal days 2-10 (P2-P10), attenuated during development, and finally disappeared in the mature hippocampus. Heterosynaptic LTD of excitatory postsynaptic currents in the developing hippocampus was expressed presynaptically, spread to neighboring neurons, and was mediated by eCBs. Heterosynaptic LTD of field excitatory postsynaptic potentials was associated with a decrease in fiber volley amplitude with a similar time course. Depression of fiber volleys was blocked by K(+) channel block...

Research paper thumbnail of Brain-derived neurotrophic factor increases inhibitory synapses, revealed in solitary neurons cultured from rat visual cortex

Neuroscience, 2004

To elucidate chronic actions of brain-derived neurotrophic factor (BDNF) on GABAergic synapses, w... more To elucidate chronic actions of brain-derived neurotrophic factor (BDNF) on GABAergic synapses, we examined effects of a long-term application of BDNF for 10-15 days on autapses (synapses) of solitary GABAergic neurons cultured from rat visual cortex. Solitary neuron preparations were used to exclude a possible contamination of BDNF actions on excitatory neurons in dissociated neuron culture or slice preparations. Neurons were confirmed to be GABAergic pharmacologically with bicuculline, a selective antagonist for GABAA receptors and immunocytochemically with antibody against glutamic acid decarboxylase 65, a GABA synthesizing enzyme. To evaluate GABAergic synaptic function, evoked and/or miniature inhibitory postsynaptic currents (IPSCs) were recorded in the whole-cell voltage-clamp mode. The treatment with BDNF at a concentration of 100 ng/ml enhanced the amplitude of evoked IPSCs and the frequency of miniature IPSCs. In contrast, BDNF did not have a detectable effect on the ampli...

Research paper thumbnail of Electrophysiological Technique for Analysis of Synaptic Function of PKN1 in Hippocampus

Research paper thumbnail of S1-4 Roles of calcium and calcium/calmodulin-dependent phosphatase in the induction of long-term potentiation/depression in visual cortical slices of rats

Neuroscience Research Supplements, 1993

Research paper thumbnail of Lateral distribution of hypothalamic signals controlling thermoregulatory vasomotor activity and shivering in rats

The American journal of physiology

The present study explored the laterality of central nervous thermoregulatory control in anesthet... more The present study explored the laterality of central nervous thermoregulatory control in anesthetized rats by measuring paw skin vasomotor activity and cold-induced shivering in hind leg muscles during unilateral preoptic area and anterior hypothalamus (POAH) warming and electrical stimulation or during unilateral thermal stimulation of abdominal skin. Unilateral POAH warming produced vasodilation on both sides of the body, but vasodilation on the ipsilateral side always either occurred at a lower threshold hypothalamic temperature or was stronger than on the contralateral side. In a cold environment (5 degrees C), shivering was suppressed simultaneously in both hind legs when one side of the POAH was warmed, and shivering reappeared simultaneously on both sides when POAH warming stopped. These results suggest that different thermoregulatory effectors are regulated in a different way by each side of the POAH. Unilateral thermal stimulation of the abdominal skin, on the other hand, a...

Research paper thumbnail of Modes of action of local hypothalamic and skin thermal stimulation on salivary secretion in rats

The Journal of Physiology, 1990

In urethane or ketamine-anaesthetized rats, salivary secretion was observed when local brain site... more In urethane or ketamine-anaesthetized rats, salivary secretion was observed when local brain sites or trunk skin were stimulated thermally or electrically.

Research paper thumbnail of Ipsilateral hypothalamic control of thermally induced salivary secretion in rats

Neuroscience Research Supplements, 1989

Research paper thumbnail of Salivary secretion and grooming behaviour during heat exposure in freely moving rats

The Journal of Physiology, 1991

1. At neutral (24°C) and at hot (40°C) ambient temperatures (TR) salivary secretion from the subm... more 1. At neutral (24°C) and at hot (40°C) ambient temperatures (TR) salivary secretion from the submandibular gland of freely moving rats was recorded, together with simultaneous observation of saliva-spreading behaviour (grooming).

Research paper thumbnail of A switching role of postsynaptic calcium in the induction of long-term potentiation or long-term depression in visual cortex

Seminars in Neuroscience, 1996

Long-term potentiation (LTP) and depression (LTD) are considered to be an initial step in process... more Long-term potentiation (LTP) and depression (LTD) are considered to be an initial step in processes governing experience-dependent changes in neuronal function in cerebral neocortex. As a mechanism for the induction of LTP and LTD, it is hypothesized that an input-associated rise of Ca 2 + beyond a certain threshold at postsynaptic sites leads to LTP while a lower rise below the threshold leads to LTD. To test this Ca 2 + -switching hypothesis, the method of microscopic fluorometry with Ca 2 + indicators such as fura-2 has been employed. In this review, problems with this fura-2 method are described, and results obtained with other indicators having weaker Ca 2 + -chelating action are mentioned briefly.

Research paper thumbnail of Brain-Derived Neurotrophic Factor Prevents Low-Frequency Inputs from Inducing Long-Term Depression in the Developing Visual Cortex

The Journal of Neuroscience, Mar 15, 1999

Brain-derived neurotrophic factor (BDNF) is reported to enhance synaptic transmission and to play... more Brain-derived neurotrophic factor (BDNF) is reported to enhance synaptic transmission and to play a role in long-term potentiation in hippocampus and neocortex. If so, a shortage or blockade of BDNF might lead to another form of synaptic plasticity, long-term depression (LTD). To test this possibility and to elucidate mechanisms if it is the case, EPSCs evoked by test stimulation of layer IV were recorded from layer II/III neurons in visual cortical slices of young rats in the whole-cell voltage-clamp mode. LTD was induced by low-frequency stimulation (LFS) at 1 Hz for 10-15 min if each pulse of the LFS was paired with depolarization of neurons to Ϫ30 mV but was not induced if their membrane potentials were kept at Ϫ70 mV. Such an LTD was blocked by exogenously applied BDNF, probably through presynaptic mechanisms. Suppression of endogenous BDNF activity by the anti-BDNF antibody or an inhibitor for BDNF receptors made otherwise ineffective stimuli (LFS without postsynaptic depolarization) effective for LTD induction, suggesting that endogenous BDNF may prevent low-frequency inputs from inducing LTD in the developing visual cortex.

Research paper thumbnail of An increase in calcium through NMDA receptors in apical dendrites of layer II/III neurons of rat visual cortex

Research paper thumbnail of S3-2 Simultaneous measurements of synaptic input-induced calcium rise and changes in synaptic efficacy in cortical neurons loaded with a low-affinity Ca 2+ indicator

Neurosci Res, 1996

To test the hypothesis that long-term potentiation (LTP) is induced if an increase in Gas+ concen... more To test the hypothesis that long-term potentiation (LTP) is induced if an increase in Gas+ concentration at postsynaptic sites during tetanic synaptic inputs is higher than the certain threshold, while long-term depression (LTD) is induced if it is below the threshold, one can use microscopic fluorometry with a fluorescent Ca2+ indicator. Since high-affinity Ca2+ indicators such as fura-may interfere with physiological processes for the induction of LTP or LTD, we used another indicator, rhod-2 which has a much weaker chelating action than fura-2. Initially, rhodG/AM (membrane-permeable type) was applied to visual cortical slices of young rats. Field responses to test stimulation of layer IV of the cortex were recorded from layer ll/lll. Fluorescent signal of rhod-2 was detected through a window (50 x 50 urn) placed near the recording electrode in layer ll/lll. In slices in which LTP of field responses was induced by tetanic stimulation of layer IV, tetanus-induced rise in fluorescent signal was significantly larger than that in LTD-induced slices. Next, we injected rhod-2 directly into pyramidal-cell like neurons of layer ll/lll through a patch pipette from which excitatory postsynaptic potentials (EPSPs) were recorded. During tetanic stimulation, we often observed a marked increase in fluorescence intensity at apical dendritic areas about 50 urn distal from the soma. In neurons in which LTP of EPSPs was induced, the fluorescent increase at this area was significantly larger than that in neurons in which LTD was observed. These results seem to be consistent with the above-mentioned hypothesis.

Research paper thumbnail of 309 An increase in calcium through NMDA receptors in apical dendrites of layer II/III neurons of rat visual cortex

Neurosci Res, 1997

The possibility that NMDA receptors participate in input-induced Ca2+ rise at postsynaptic sites ... more The possibility that NMDA receptors participate in input-induced Ca2+ rise at postsynaptic sites was tested with whole-cell patch-clamp recording and fluorescent Ca2+ imaging in layer II/III pyramidal neurons of rat visual cortex . In the current-clamp mode, high-frequency stimulation of layer IV induced a prominent rise in fluorescence at apical dendritic sites 30-120um from the soma. Such a rise was reduced by a NMDA receptor antagonist, APV, by about 40% in 9 of 15 neurons. In Mg2+ -free medium the local Ca2+ rise in dendrites was induced by synaptic inputs in neurons which were clamped at -8OmV, and this rise was blocked by APV. A local fluorescence rise was also detected in neurons clamped at +lOmV, at which voltage-dependent Ca2+ channels should not be activated by synaptic inputs. This rise was blocked by APV. These results suggest that NMDA receptors contribute to the local Ca2+ rise induced by synaptic inputs in apical dendrites of layer II/III neurons in the cortex.

Research paper thumbnail of S1-4 Roles of calcium and calcium/calmodulin-dependent phosphatase in the induction of long-term potentiation/depression in visual cortical slices of rats

Neuroscience Research Supplements, 1993

Research paper thumbnail of Long-term depression in rat visual cortex is associated with a lower rise of postsynaptic calcium than long-term potentiation

Neuroscience Research, 1996

To test the hypothesis that an input-associated rise of Ca2+ at postsynaptic sites beyond a certa... more To test the hypothesis that an input-associated rise of Ca2+ at postsynaptic sites beyond a certain threshold leads to the induction of long-term potentiation (LTP) while a lower rise below the threshold leads to long-term depression (LTD), the method of microscopic Ca2+ fluorometry was employed simultaneously with recordings of synaptic activity from layer II/III of visual cortical slices prepared from young rats. The conventional Ca2+ indicators, such as fura-2 or fluo-3, may interfere with intracellular processes for the induction of LTP/LTD because of their strong Ca(2+)-chelating action. To minimize such a problem, another Ca2+ indicator, rhod-2, was used since it has a much weaker Ca(2+)-chelating action than those indicators. In 16 slices loaded with rhod-2 through the perfusion medium, tetanic stimulation of theta-burst type was applied to layer IV of the cortex and changes in Ca2+ concentration were analyzed in layer II/III from which field potentials to test stimulation of layer IV were recorded simultaneously. In 7 slices in which weak tetanic stimulation consisting of 0.1 ms duration pulses was applied to layer IV, LTD of field responses was induced, while LTP was induced in 6 of the 9 slices in which strong tetanus consisting of 0.2 ms pulses was applied. In the 6 slices in which LTP was induced, the peak rise of fluorescence intensity during tetanus was 13.9 +/- 0.2 (S.E.M.) %, which was significantly (t-test, P < 0.01) higher than that (10.4 +/- 0.3%) in the 9 slices in which LTD was induced. In another series of experiments, rhod-2 was injected directly into 12 pyramidal cell-like neurons in layer II/III through patch pipettes, and changes in Ca2+ concentration in apical dendritic areas during tetanus were measured simultaneously with recordings of excitatory postsynaptic potentials (EPSPs) evoked by test stimulation of layer IV. It was found that LTP of EPSPs was induced in 4 cells which exhibited a strong rise of dendritic Ca2+ signal (197.1 +/- 18.5%) while LTD was induced in other 5 cells which showed a weak rise of the signal (31.0 +/- 4.1%). These results seem consistent with the above-mentioned, Ca(2+)-switching hypothesis for the induction of LTP and LTD in visual cortex.

Research paper thumbnail of Turning on of CICR in LTD induction after critical period of NR2 subunits switch

Neuroscience Research, 2011

Abstracts / Neuroscience Research 71S (2011) e108-e415 e219 found that the relationship was enhan... more Abstracts / Neuroscience Research 71S (2011) e108-e415 e219 found that the relationship was enhanced in SDRs, indicating that the efficacy of basal synaptic transmission was increased. Western blot analysis showed that there was no significant difference in the expression of GluA1, GluA2, PSD95 and presynaptic proteins between SDRs and control rats. However, the expression of NMDAR subunits, GluN1, GluN2A and GluN2B, was increased in the CA1 region of SDRs. Correspondingly, SDRs showed an increase in the ratio of NMDAR-to AMPAR-mediated synaptic currents in whole-cell patchclamp recordings from CA1 pyramidal cells. Furthermore, SDRs exhibited enhanced LTP induced by tetanic stimulation, as expected from the increased NMDAR expression. Taken together, our results suggest that GH regulates the expression of NMDA receptors in the hippocampus, which may result in modification of abilities of learning and memory in the whole animal.

Research paper thumbnail of S3-2 Simultaneous measurements of synaptic input-induced calcium rise and changes in synaptic efficacy in cortical neurons loaded with a low-affinity Ca2+ indicator

Neuroscience Research, 1996

To test the hypothesis that long-term potentiation (LTP) is induced if an increase in Gas+ concen... more To test the hypothesis that long-term potentiation (LTP) is induced if an increase in Gas+ concentration at postsynaptic sites during tetanic synaptic inputs is higher than the certain threshold, while long-term depression (LTD) is induced if it is below the threshold, one can use microscopic fluorometry with a fluorescent Ca2+ indicator. Since high-affinity Ca2+ indicators such as fura-may interfere with physiological processes for the induction of LTP or LTD, we used another indicator, rhod-2 which has a much weaker chelating action than fura-2. Initially, rhodG/AM (membrane-permeable type) was applied to visual cortical slices of young rats. Field responses to test stimulation of layer IV of the cortex were recorded from layer ll/lll. Fluorescent signal of rhod-2 was detected through a window (50 x 50 urn) placed near the recording electrode in layer ll/lll. In slices in which LTP of field responses was induced by tetanic stimulation of layer IV, tetanus-induced rise in fluorescent signal was significantly larger than that in LTD-induced slices. Next, we injected rhod-2 directly into pyramidal-cell like neurons of layer ll/lll through a patch pipette from which excitatory postsynaptic potentials (EPSPs) were recorded. During tetanic stimulation, we often observed a marked increase in fluorescence intensity at apical dendritic areas about 50 urn distal from the soma. In neurons in which LTP of EPSPs was induced, the fluorescent increase at this area was significantly larger than that in neurons in which LTD was observed. These results seem to be consistent with the above-mentioned hypothesis.

Research paper thumbnail of 309 An increase in calcium through NMDA receptors in apical dendrites of layer II/III neurons of rat visual cortex

Neuroscience Research, 1997

The possibility that NMDA receptors participate in input-induced Ca2+ rise at postsynaptic sites ... more The possibility that NMDA receptors participate in input-induced Ca2+ rise at postsynaptic sites was tested with whole-cell patch-clamp recording and fluorescent Ca2+ imaging in layer II/III pyramidal neurons of rat visual cortex . In the current-clamp mode, high-frequency stimulation of layer IV induced a prominent rise in fluorescence at apical dendritic sites 30-120um from the soma. Such a rise was reduced by a NMDA receptor antagonist, APV, by about 40% in 9 of 15 neurons. In Mg2+ -free medium the local Ca2+ rise in dendrites was induced by synaptic inputs in neurons which were clamped at -8OmV, and this rise was blocked by APV. A local fluorescence rise was also detected in neurons clamped at +lOmV, at which voltage-dependent Ca2+ channels should not be activated by synaptic inputs. This rise was blocked by APV. These results suggest that NMDA receptors contribute to the local Ca2+ rise induced by synaptic inputs in apical dendrites of layer II/III neurons in the cortex.

Research paper thumbnail of Imaging of calcineurin activated by long-term depression-inducing synaptic inputs in living neurons of rat visual cortex

European Journal of Neuroscience, 2003

Long-term depression (LTD) of synaptic transmission is induced by low-frequency stimulation (LFS)... more Long-term depression (LTD) of synaptic transmission is induced by low-frequency stimulation (LFS) of afferents lasting for a long time, typically for 10±15 min, in neocortical and hippocampal slices. It is suggested that calcineurin, Ca 2 /calmodulin-dependent protein phosphatase, plays a role in the induction of LTD, based on the results that pharmacological or genetic manipulation of calcineurin activity interfered in its induction. However, questions as to why it takes so long to induce LTD and in which compartment of neurons calcineurin is activated remain unanswered. With a¯uorescent indicator for calcineurin activity, we visualized the spatiotemporal pattern of its activation in living neurons in layer II/III of visual cortical slices of rats during the LFS of layer IV that induced LTD of synaptic responses. During LFS, the¯uorescence intensity gradually increased with a latency of a few minutes in dendrites and soma of neurons, and remained increased during the whole observation period (10±25 min) after LFS. The onset latency of the increase in the soma was slower than that in the distal dendritic region. The LFS-induced rise in¯uorescence was not observed in neurons which were loaded with inhibitors of calcineurin, indicating that the intensity of¯uorescence re¯ects calcineurin activity. Control stimulation at 0.05 Hz and y-burst stimulation did not signi®cantly change the intensity of¯uorescence. Only LFS-type inputs effectively activate calcineurin in postsynaptic neurons in an augmenting manner, and such a time-consuming activation of calcineurin may be a reason why long-lasting LFS is necessary for the induction of LTD.

Research paper thumbnail of PSD-Zip70 Deficiency Causes Prefrontal Hypofunction Associated with Glutamatergic Synapse Maturation Defects by Dysregulation of Rap2 Activity

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 21, 2015

Dysregulation of synapse formation and plasticity is closely related to the pathophysiology of ps... more Dysregulation of synapse formation and plasticity is closely related to the pathophysiology of psychiatric and neurodevelopmental disorders. The prefrontal cortex (PFC) is particularly important for executive functions such as working memory, cognition, and emotional control, which are impaired in the disorders. PSD-Zip70 (Lzts1/FEZ1) is a postsynaptic density (PSD) protein predominantly expressed in the frontal cortex, olfactory bulb, striatum, and hippocampus. Here we found that PSD-Zip70 knock-out (PSD-Zip70KO) mice exhibit working memory and cognitive defects, and enhanced anxiety-like behaviors. These abnormal behaviors are caused by impaired glutamatergic synapse transmission accompanied by tiny-headed immature dendritic spines in the PFC, due to aberrant Rap2 activation, which has roles in synapse formation and plasticity. PSD-Zip70 modulates the Rap2 activity by interacting with SPAR (spine-associated RapGAP) and PDZ-GEF1 (RapGEF) in the postsynapse. Furthermore, suppression...

Research paper thumbnail of Regulation of excitability and plasticity by endocannabinoids and PKA in developing hippocampus

Proceedings of the National Academy of Sciences of the United States of America, Jan 26, 2008

The activity-dependent strengthening and weakening of synaptic transmission are hypothesized to b... more The activity-dependent strengthening and weakening of synaptic transmission are hypothesized to be the basis of not only memory and learning but also the refinement of neural circuits during development. Here we report that, in the developing CA1 area of the hippocampus, endocannabinoid (eCB)-mediated heterosynaptic long-term depression (LTD) of glutamatergic excitatory synaptic transmission is associated with PKA-mediated homosynaptic long-term potentiation (LTP). This form of LTD was dominant at postnatal days 2-10 (P2-P10), attenuated during development, and finally disappeared in the mature hippocampus. Heterosynaptic LTD of excitatory postsynaptic currents in the developing hippocampus was expressed presynaptically, spread to neighboring neurons, and was mediated by eCBs. Heterosynaptic LTD of field excitatory postsynaptic potentials was associated with a decrease in fiber volley amplitude with a similar time course. Depression of fiber volleys was blocked by K(+) channel block...

Research paper thumbnail of Brain-derived neurotrophic factor increases inhibitory synapses, revealed in solitary neurons cultured from rat visual cortex

Neuroscience, 2004

To elucidate chronic actions of brain-derived neurotrophic factor (BDNF) on GABAergic synapses, w... more To elucidate chronic actions of brain-derived neurotrophic factor (BDNF) on GABAergic synapses, we examined effects of a long-term application of BDNF for 10-15 days on autapses (synapses) of solitary GABAergic neurons cultured from rat visual cortex. Solitary neuron preparations were used to exclude a possible contamination of BDNF actions on excitatory neurons in dissociated neuron culture or slice preparations. Neurons were confirmed to be GABAergic pharmacologically with bicuculline, a selective antagonist for GABAA receptors and immunocytochemically with antibody against glutamic acid decarboxylase 65, a GABA synthesizing enzyme. To evaluate GABAergic synaptic function, evoked and/or miniature inhibitory postsynaptic currents (IPSCs) were recorded in the whole-cell voltage-clamp mode. The treatment with BDNF at a concentration of 100 ng/ml enhanced the amplitude of evoked IPSCs and the frequency of miniature IPSCs. In contrast, BDNF did not have a detectable effect on the ampli...