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The role of extrasynaptic NMDARs in LTP induction
Abstracts / Neuroscience Research 68S (2010) e55–e108
e87
to the same level in GluN2B KO and compared the blocking effect of ventral elimination between the two types of KO mice.
O2-3-3-3 Charactarization of STDP at L4-L2/3 and its development in the barrel cortex
doi:10.1016/j.neures.2010.07.147
Fumitaka Kimura 1 , Chiaki Itami 2 1 2
O2-3-3-1 Regulation of Inhibitory Synaptic Plasticity by Temporal Sequence of Ca2+ Signals in a Cerebellar Purkinje Neuron Shin-ya Kawaguchi , Tomoo Hirano Dept Biophys, Grad Sch Sci, Kyoto Univ, Kyoto Most forms of synaptic plasticity are induced by the increase in intracellular Ca2+ concentration ([Ca2+ ]i ). However, it remains elusive how the temporal pattern of [Ca2+ ]i increase affects synaptic plasticity. Here, by combined application of systems biological model simulation and whole-cell patch clamp recording, we show that the temporal pattern of Ca2+ signal dynamically regulates whether the plasticity is induced or not. At GABAergic synapses on a cerebellar Purkinje neuron, postsynaptic depolarization induces long-term potentiation of GABAA R-mediated inhibitory synaptic transmission, called rebound potentiation (RP). The RP induction requires postsynaptic [Ca2+ ]i increase and the resultant activation of Ca2+ /calmodulin-dependent protein kinase II (CaMKII). We previously developed a kinetic simulation model of signaling cascades regulating RP, and demonstrated that sustained CaMKII activation triggered by [Ca2+ ]i increase underlies the RP establishment. Here, we show that either of two different patterns of [Ca2+ ]i increase, one with short duration and large amplitude and the other long and small, efficiently activates CaMKII inducing RP. However, simulation suggests that the sustained CaMKII activation is suppressed when these two patterns of [Ca2+ ]i increase are temporally sequenced. Interestingly, the suppressive effect is evident only when the strong [Ca2+ ]i increase precedes the weak one. Thus, the model predicts that the RP induction depends not only on the amplitude of [Ca2+ ]i increase but also on its context. This prediction was validated by electrophysiological experiments on cultured Purkinje neurons. We also show the molecular mechanism underlying the context-dependency of RP induction.
Dept Molecular Neuroscience, Osaka University Grad. Sch. of Medicine Dept Physiol. Fac. Med. Saitama Med. University, Moroyama, Japan
The rodent barrel cortex shows remarkable plasticity. During the development, there exists two distinct plasticity: one is at thalamocortical synapse that ends before P5, the other starts from around the end of the 2nd postnatal week. Thus, there is a gap of about a week. One important feature of the 2nd plasticity is that the direction and the extent of plasticity depends on the spike timings of pre- and postsynaptic cells, which is called spike timing dependent plasticity, or STDP. We recently reported that feedforward inhibition via L4 FS cells plays an important role in regulating the spike sequences of “L4 leading L2/3”, which is established only after the end of the 2nd postnatal week. In addition to these types of plasticity, we recently reported that LTP could still be induced during the 2nd postnatal week, in which both “pre followed by post” and “post followed by pre” stimulations lead to significant potentiation. This LTP does not depend on spike seuqueces but its maginitude still depends on spike timing, thus, it is a distinct type of STDP. To further characterize this new type of STDP, we tested its dependece on NMDA-R and postsynaptic rise in Ca, and if it required PKA or CaMKII activation. Moreover, to understand the transition of LTP to LTD by “post-pre” stimulation occurring around the 2nd postnatal week, we tested to see any changes in the sensitibity to a cannabinoid agonist. Since the 2nd postnatal week is the time for L4 cells to innervate L2/3, such STDP of bilateral potentiation may be beneficial for L4 cell and the physiological significance of the switch from bilateral to biphasic STDP will be discussed. doi:10.1016/j.neures.2010.07.150
O2-3-3-4 A hypothesis of efficient dopamine-dependent metaplasticity
learning
rule:
Yutaka Sakai Brain Science Institute, Tamagawa University, Tokyo
doi:10.1016/j.neures.2010.07.148
O2-3-3-2 The role of extrasynaptic NMDARs in LTP induction Sheng-tian Li , Qian Yang, Jue-gang Ju, Yixin Xiao, Yue Zhang, Gong Ju School of Life Science & Biotechnology, Shanghai Jiao Tong Univ, China
Selectivity of each neuron to specific input patterns is a significant property for a neural network in order to perform a function. Acquisition of neuronal selectivity from experience needs a mechanism to enlarge slight difference in synaptic strength caused by statistical fluctuation. However, it is known that spike-timing-dependent synaptic plasticity (STDP) also depends on the initial strength of the synapse before pairing stimuli(Bi and Poo 1998). The size of long-term potentiation (LTP) is approximately independent of the initial strength, while the size of long-term depression (LTD) is approximately proportional to the initial strength. This fact implies that LTP be dominant for a weak synapse and that LTD be dominant for a strong synapse. Namely each synapse is subject to the strong force field to converge in a balance point. In such force field, slight difference in synaptic strength caused by statistical fluctuation would vanishes. Therefore, neuronal selectivity can never be acquired by such a strength-dependent synaptic learning rule. In order to overcome this problem, this work applied a neurotransmitter-dependent metaplasticity rule to strength-dependent STDP and demonstrated that a model neuron can acquire selectivity to specific synapses even though statistics of inputs to individual synapses are identical. In addition, if the neurotransmitterrelease is considered as a reinforcement signal reflecting behavioral reward (e.g. dopamine), then the metaplasticity rule can reinforce the synapses which contribute reward given after a few seconds delay. Namely, the proposed learning rule can overcome the so-called distal reward problem.
N-methyl-D-aspartate receptor (NMDAR) plays an important role in the induction of long-term potentiation (LTP) at hippocampal cornu ammonis 1 (CA1) synapse. Several studies have indicated the opposing role of synaptic NMDARs (S-NMDARs) and extrasynaptic NMDARs (ES-NMDARs) in cAMP response element binding protein-dependent gene regulation, neuronal survival/death, and regulation of extracellular signal-regulated kinases activity in cultured hippocampal neurons. Whether the S-NMDARs and ES-NMDARs differentially contribute to LTP induction, however, remains controversial. Using irreversible use-dependent NMDAR antagonist MK-801, we succeed in selective inactivation of synaptic NMDARs in CA 1 neurons of adult mice hippocampal slices. Subsequent activation of ES-NMDARs by a 3-train high-frequency stimulation failed to induce LTP, whereas the same protocol evoked LTP in slices treated with antagonists of NR2B subunit. Coordinately, selective activation of S-NMDARs by a short train of 5 Hz stimulation, which does not cause any long-term changes in synaptic efficacy per-se, also induces LTP when the NR2B subunit is blocked. Taking together, these data demonstrate that both synaptic and extrasynaptic NR2B-containing NMDARs make negative contribution to LTP induction. We also provides here that balance of NR2A- and NR2B activation on synaptic- or extrasynaptic sites directs the induction of LTP.
O2-3-4-1 Melatonin inhibits hippocampal LTP via nitric oxide signaling pathway
doi:10.1016/j.neures.2010.07.149
Yoshiyuki Takahashi 1 , Takashi Okada 2
doi:10.1016/j.neures.2010.07.151
1
Dept Psychology, Sophia Univ, Tokyo 2 Dept Psychology, Sophia Univ, Tokyo
Hippocampal long-term potentiation (LTP) is considered a potent candidate for the physiological basis of learning and memory, and previous studies reported that learning performance and hippocampal LTP show a circadian rhythm. Since a pineal hormone melatonin shows a circadian secretion pattern and indeed melatonin reportedly reduced the magnitude of hippocampal LTP, melatonin is a candidate of the endogenous regulator of hippocampal LTP with circadian rhythm. To clarify the cellular mechanisms
e87
to the same level in GluN2B KO and compared the blocking effect of ventral elimination between the two types of KO mice.
O2-3-3-3 Charactarization of STDP at L4-L2/3 and its development in the barrel cortex
doi:10.1016/j.neures.2010.07.147
Fumitaka Kimura 1 , Chiaki Itami 2 1 2
O2-3-3-1 Regulation of Inhibitory Synaptic Plasticity by Temporal Sequence of Ca2+ Signals in a Cerebellar Purkinje Neuron Shin-ya Kawaguchi , Tomoo Hirano Dept Biophys, Grad Sch Sci, Kyoto Univ, Kyoto Most forms of synaptic plasticity are induced by the increase in intracellular Ca2+ concentration ([Ca2+ ]i ). However, it remains elusive how the temporal pattern of [Ca2+ ]i increase affects synaptic plasticity. Here, by combined application of systems biological model simulation and whole-cell patch clamp recording, we show that the temporal pattern of Ca2+ signal dynamically regulates whether the plasticity is induced or not. At GABAergic synapses on a cerebellar Purkinje neuron, postsynaptic depolarization induces long-term potentiation of GABAA R-mediated inhibitory synaptic transmission, called rebound potentiation (RP). The RP induction requires postsynaptic [Ca2+ ]i increase and the resultant activation of Ca2+ /calmodulin-dependent protein kinase II (CaMKII). We previously developed a kinetic simulation model of signaling cascades regulating RP, and demonstrated that sustained CaMKII activation triggered by [Ca2+ ]i increase underlies the RP establishment. Here, we show that either of two different patterns of [Ca2+ ]i increase, one with short duration and large amplitude and the other long and small, efficiently activates CaMKII inducing RP. However, simulation suggests that the sustained CaMKII activation is suppressed when these two patterns of [Ca2+ ]i increase are temporally sequenced. Interestingly, the suppressive effect is evident only when the strong [Ca2+ ]i increase precedes the weak one. Thus, the model predicts that the RP induction depends not only on the amplitude of [Ca2+ ]i increase but also on its context. This prediction was validated by electrophysiological experiments on cultured Purkinje neurons. We also show the molecular mechanism underlying the context-dependency of RP induction.
Dept Molecular Neuroscience, Osaka University Grad. Sch. of Medicine Dept Physiol. Fac. Med. Saitama Med. University, Moroyama, Japan
The rodent barrel cortex shows remarkable plasticity. During the development, there exists two distinct plasticity: one is at thalamocortical synapse that ends before P5, the other starts from around the end of the 2nd postnatal week. Thus, there is a gap of about a week. One important feature of the 2nd plasticity is that the direction and the extent of plasticity depends on the spike timings of pre- and postsynaptic cells, which is called spike timing dependent plasticity, or STDP. We recently reported that feedforward inhibition via L4 FS cells plays an important role in regulating the spike sequences of “L4 leading L2/3”, which is established only after the end of the 2nd postnatal week. In addition to these types of plasticity, we recently reported that LTP could still be induced during the 2nd postnatal week, in which both “pre followed by post” and “post followed by pre” stimulations lead to significant potentiation. This LTP does not depend on spike seuqueces but its maginitude still depends on spike timing, thus, it is a distinct type of STDP. To further characterize this new type of STDP, we tested its dependece on NMDA-R and postsynaptic rise in Ca, and if it required PKA or CaMKII activation. Moreover, to understand the transition of LTP to LTD by “post-pre” stimulation occurring around the 2nd postnatal week, we tested to see any changes in the sensitibity to a cannabinoid agonist. Since the 2nd postnatal week is the time for L4 cells to innervate L2/3, such STDP of bilateral potentiation may be beneficial for L4 cell and the physiological significance of the switch from bilateral to biphasic STDP will be discussed. doi:10.1016/j.neures.2010.07.150
O2-3-3-4 A hypothesis of efficient dopamine-dependent metaplasticity
learning
rule:
Yutaka Sakai Brain Science Institute, Tamagawa University, Tokyo
doi:10.1016/j.neures.2010.07.148
O2-3-3-2 The role of extrasynaptic NMDARs in LTP induction Sheng-tian Li , Qian Yang, Jue-gang Ju, Yixin Xiao, Yue Zhang, Gong Ju School of Life Science & Biotechnology, Shanghai Jiao Tong Univ, China
Selectivity of each neuron to specific input patterns is a significant property for a neural network in order to perform a function. Acquisition of neuronal selectivity from experience needs a mechanism to enlarge slight difference in synaptic strength caused by statistical fluctuation. However, it is known that spike-timing-dependent synaptic plasticity (STDP) also depends on the initial strength of the synapse before pairing stimuli(Bi and Poo 1998). The size of long-term potentiation (LTP) is approximately independent of the initial strength, while the size of long-term depression (LTD) is approximately proportional to the initial strength. This fact implies that LTP be dominant for a weak synapse and that LTD be dominant for a strong synapse. Namely each synapse is subject to the strong force field to converge in a balance point. In such force field, slight difference in synaptic strength caused by statistical fluctuation would vanishes. Therefore, neuronal selectivity can never be acquired by such a strength-dependent synaptic learning rule. In order to overcome this problem, this work applied a neurotransmitter-dependent metaplasticity rule to strength-dependent STDP and demonstrated that a model neuron can acquire selectivity to specific synapses even though statistics of inputs to individual synapses are identical. In addition, if the neurotransmitterrelease is considered as a reinforcement signal reflecting behavioral reward (e.g. dopamine), then the metaplasticity rule can reinforce the synapses which contribute reward given after a few seconds delay. Namely, the proposed learning rule can overcome the so-called distal reward problem.
N-methyl-D-aspartate receptor (NMDAR) plays an important role in the induction of long-term potentiation (LTP) at hippocampal cornu ammonis 1 (CA1) synapse. Several studies have indicated the opposing role of synaptic NMDARs (S-NMDARs) and extrasynaptic NMDARs (ES-NMDARs) in cAMP response element binding protein-dependent gene regulation, neuronal survival/death, and regulation of extracellular signal-regulated kinases activity in cultured hippocampal neurons. Whether the S-NMDARs and ES-NMDARs differentially contribute to LTP induction, however, remains controversial. Using irreversible use-dependent NMDAR antagonist MK-801, we succeed in selective inactivation of synaptic NMDARs in CA 1 neurons of adult mice hippocampal slices. Subsequent activation of ES-NMDARs by a 3-train high-frequency stimulation failed to induce LTP, whereas the same protocol evoked LTP in slices treated with antagonists of NR2B subunit. Coordinately, selective activation of S-NMDARs by a short train of 5 Hz stimulation, which does not cause any long-term changes in synaptic efficacy per-se, also induces LTP when the NR2B subunit is blocked. Taking together, these data demonstrate that both synaptic and extrasynaptic NR2B-containing NMDARs make negative contribution to LTP induction. We also provides here that balance of NR2A- and NR2B activation on synaptic- or extrasynaptic sites directs the induction of LTP.
O2-3-4-1 Melatonin inhibits hippocampal LTP via nitric oxide signaling pathway
doi:10.1016/j.neures.2010.07.149
Yoshiyuki Takahashi 1 , Takashi Okada 2
doi:10.1016/j.neures.2010.07.151
1
Dept Psychology, Sophia Univ, Tokyo 2 Dept Psychology, Sophia Univ, Tokyo
Hippocampal long-term potentiation (LTP) is considered a potent candidate for the physiological basis of learning and memory, and previous studies reported that learning performance and hippocampal LTP show a circadian rhythm. Since a pineal hormone melatonin shows a circadian secretion pattern and indeed melatonin reportedly reduced the magnitude of hippocampal LTP, melatonin is a candidate of the endogenous regulator of hippocampal LTP with circadian rhythm. To clarify the cellular mechanisms