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Electrophysiological and behavioral analysis of gene-targeted mice to understand mechanisms of learning and memory
S18
Abstracts / Neuroscience Research 58S (2007) S1–S244
S2A-K5 Dendritic design implements algorithm for extraction
S3A-A3 Reconfiguration of synaptic network and enhancement
of sensory information in insect sensory interneuron
of memory by magnesium ion
Hiroto Ogawa Department of Biology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
Guosong Liu 1,2 1 Center for Learning and Memory, School of Medicine, Tsinghua Univerisity, Beijing, China; 2 Center for Learning and Memory, University of Texas, Austin, USA
While sensory information is encoded by firing pattern of individual sensory neurons, it is also represented by spatio-temporal patterns of activity in population of neurons. For example, directions of air-current surrounding the cricket are represented by the spatial patterns in ensemble activities of mechanosensory afferents. Postsynaptic sensory interneurons must decode these population responses and extract the directional information reliably. We examined how identified sensory interneurons decode the directional information represented by population of sensory afferents, using simultaneous imaging of pre- and postsynaptic Ca2+ signals. Two types of the sensory interneurons, which have different dendritic design in electrotonic distances from dendritic branches to a spike-initiating zone, displayed different behavior for extraction of directional tuning property from the sensory afferents. It is possible that the differences in distribution of synaptic weights due to the dendritic geometry could be related to ‘decoding algorithm’ of sensory information in the sensory interneurons.
Learning and memory are the one of fundamental capability of brain. Yet little is known about the endogenous molecules regulating this capability. Here, we show that increasing magnesium consumption in intact animal enhances learning and memory function of rats in different aging. At the level of neuronal connections, elevated magnesium triggers a redistribution of synaptic weights on dendritic tree from fewer numbers of strong synapses to lager number of weaker synapses. This synaptic reconfiguration enables a selective enhancement of excitatory synaptic transmission for correlated inputs during coincident detection, while keeping it constant for uncorrelated inputs. This, coupled with upregulation of NR2B-containing NMDARs, enhances the capacity of the synaptic network for modification by correlated inputs. Our findings suggest that magnesium is a key regulator of a proper synaptic configuration essential for memory function.
Research fund: KAKENHI16570068
S3A-A1 Mechanisms of memory formation by transcription factors Satoshi Kida Department of Bioscience, Tokyo University of Agriculture, Japan Gene expression regulation plays crucial roles in memory formation. To understand the mechanisms of memory formation from the view of gene expression regulation, we are investigating roles of transcription factors in memory formation using conditional mutant mice. CREB is phosphorylated at Serine 133 by cAMP and Ca2+ -dependent kinases and activates CRE-mediated transcription through the interaction with coactivator CBP. Recent our studies using two transgenic mice expressing dominant active CREB mutant (CREB Y134F or CREB DIEDML) showed that facilitation of interaction of CREB–CBP enhances LTP and memory formation. Taken together with our previous observation that inhibition of this interaction blocks memory formation, we are concluding that CREB–CBP interaction functions as a molecular switch to form memory. To further understand the contribution of transcription factors for memory formation and molecular network among them, we generated conditional mutant mice of several transcription factors and are investigating the roles of them in the processes of learning and memory formation.
S3A-A4
Symptomatic treatment for Alzheimer’s disease: Enhancing cholinergic function
Paul F. Chapman, Darrel J. Pemberton, Woei Shin Chen, Zeenat Atcha, Fong Kuan Wong GSK Centre for Cognitive and Neurodegenerative Disorders, Singapore, Singapore Acetyl cholinesterase inhibitors (AChEIs) represent the current gold standard for treatment of Alzheimer’s disease (AD). Although they can provide significant benefit for patients with mild to moderate symptoms, we still need to identify treatments that will show greater efficacy and tolerability, and reach patients who do not respond to AChEIs.Validating novel targets requires the development of model systems that can predict efficacy and safety in humans. We therefore developed and/or refined protocols for testing cognitive enhancement in normal rats. Our aim was to identify tests that are sensitive to donepezil, AChEI and the leading treatment for AD. After establishing positive effects of donepezil in two tests, novel object recognition (NOR) and the Morris water maze, we tested more specific cholinergic agonists to determine whether they might also be efficacious in humans. The results indicate that specific muscarinic agonists and nicotinic a7 agonists are both capable of enhancing cognitive function in normal adult rats.
Research fund: Scientific Research on Priority Areas-Molecular Brain Science-(18022038)
S3A-A2 Electrophysiological and behavioral analysis of genetargeted mice to understand mechanisms of learning and memory Yuji Kiyama 1 , Toshiya Manabe 1,2 1 Division of Neuronal Network, Institute of Medical Science, University of Tokyo, Tokyo, Japan; 2 CREST, JST, Saitama, Japan To understand molecular and cellular mechanisms of learning and memory, combinations of genetic, electrophysiological, histological and behavioral techniques have been used. We show here some examples of gene-targeted mice that exhibit learning abnormalities as well as electrophysiological and/or histological abnormalities in some areas of the limbic system such as hippocampus and amygdala. For example, we generated mice with a knockin mutation of the tyrosine (Tyr)-1472 site to phenylalanine (Y1472F) of the NR2B subunit of the NMDA receptor. The NR2B subunit is tyrosine-phosphorylated in the brain, with Tyr-1472 its major phosphorylation site. The knockin mice showed impaired fearrelated learning and reduced amygdaloid long-term potentiation. We thus identify Tyr-1472 phosphorylation as a key mediator of fear learning and amygdaloid synaptic plasticity. Research funds: KAKENHI (17023011, 18100003) and RISTEX, JST
S3A-A5 Molecular and cellular cognition: Unraveling mechanisms of learning and memory Alcino J. Silva Department of Neurobiology, UCLA, Los Angeles, USA Our laboratory is studying the role of hippocampal and prefrontal function in recent and remote memory. We are interested in uncovering general rules for how these two brain regions account for their unique roles in recent and remote memory. We are also studying how molecular mechanisms modulate cellular responses that underlie key microcircuit properties implicated in learning and memory. To accomplish this we are using a myriad of techniques including region and temporal specific transgenic manipulations, viral vectors, pharmacology, in vivo and in vitro electrophysiology, in vivo two-photon scanning confocal microscopy, as well as a battery of behavioral tasks designed to probe hippocampal and prefrontal cortical function. Our laboratory is also interested in understanding the mechanisms underlying cognitive disorders such as those underlying learning disabilities associated with Neurofibromatosis Type 1 (NF1), Tuberous Sclerosis and schizophrenia.
Abstracts / Neuroscience Research 58S (2007) S1–S244
S2A-K5 Dendritic design implements algorithm for extraction
S3A-A3 Reconfiguration of synaptic network and enhancement
of sensory information in insect sensory interneuron
of memory by magnesium ion
Hiroto Ogawa Department of Biology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
Guosong Liu 1,2 1 Center for Learning and Memory, School of Medicine, Tsinghua Univerisity, Beijing, China; 2 Center for Learning and Memory, University of Texas, Austin, USA
While sensory information is encoded by firing pattern of individual sensory neurons, it is also represented by spatio-temporal patterns of activity in population of neurons. For example, directions of air-current surrounding the cricket are represented by the spatial patterns in ensemble activities of mechanosensory afferents. Postsynaptic sensory interneurons must decode these population responses and extract the directional information reliably. We examined how identified sensory interneurons decode the directional information represented by population of sensory afferents, using simultaneous imaging of pre- and postsynaptic Ca2+ signals. Two types of the sensory interneurons, which have different dendritic design in electrotonic distances from dendritic branches to a spike-initiating zone, displayed different behavior for extraction of directional tuning property from the sensory afferents. It is possible that the differences in distribution of synaptic weights due to the dendritic geometry could be related to ‘decoding algorithm’ of sensory information in the sensory interneurons.
Learning and memory are the one of fundamental capability of brain. Yet little is known about the endogenous molecules regulating this capability. Here, we show that increasing magnesium consumption in intact animal enhances learning and memory function of rats in different aging. At the level of neuronal connections, elevated magnesium triggers a redistribution of synaptic weights on dendritic tree from fewer numbers of strong synapses to lager number of weaker synapses. This synaptic reconfiguration enables a selective enhancement of excitatory synaptic transmission for correlated inputs during coincident detection, while keeping it constant for uncorrelated inputs. This, coupled with upregulation of NR2B-containing NMDARs, enhances the capacity of the synaptic network for modification by correlated inputs. Our findings suggest that magnesium is a key regulator of a proper synaptic configuration essential for memory function.
Research fund: KAKENHI16570068
S3A-A1 Mechanisms of memory formation by transcription factors Satoshi Kida Department of Bioscience, Tokyo University of Agriculture, Japan Gene expression regulation plays crucial roles in memory formation. To understand the mechanisms of memory formation from the view of gene expression regulation, we are investigating roles of transcription factors in memory formation using conditional mutant mice. CREB is phosphorylated at Serine 133 by cAMP and Ca2+ -dependent kinases and activates CRE-mediated transcription through the interaction with coactivator CBP. Recent our studies using two transgenic mice expressing dominant active CREB mutant (CREB Y134F or CREB DIEDML) showed that facilitation of interaction of CREB–CBP enhances LTP and memory formation. Taken together with our previous observation that inhibition of this interaction blocks memory formation, we are concluding that CREB–CBP interaction functions as a molecular switch to form memory. To further understand the contribution of transcription factors for memory formation and molecular network among them, we generated conditional mutant mice of several transcription factors and are investigating the roles of them in the processes of learning and memory formation.
S3A-A4
Symptomatic treatment for Alzheimer’s disease: Enhancing cholinergic function
Paul F. Chapman, Darrel J. Pemberton, Woei Shin Chen, Zeenat Atcha, Fong Kuan Wong GSK Centre for Cognitive and Neurodegenerative Disorders, Singapore, Singapore Acetyl cholinesterase inhibitors (AChEIs) represent the current gold standard for treatment of Alzheimer’s disease (AD). Although they can provide significant benefit for patients with mild to moderate symptoms, we still need to identify treatments that will show greater efficacy and tolerability, and reach patients who do not respond to AChEIs.Validating novel targets requires the development of model systems that can predict efficacy and safety in humans. We therefore developed and/or refined protocols for testing cognitive enhancement in normal rats. Our aim was to identify tests that are sensitive to donepezil, AChEI and the leading treatment for AD. After establishing positive effects of donepezil in two tests, novel object recognition (NOR) and the Morris water maze, we tested more specific cholinergic agonists to determine whether they might also be efficacious in humans. The results indicate that specific muscarinic agonists and nicotinic a7 agonists are both capable of enhancing cognitive function in normal adult rats.
Research fund: Scientific Research on Priority Areas-Molecular Brain Science-(18022038)
S3A-A2 Electrophysiological and behavioral analysis of genetargeted mice to understand mechanisms of learning and memory Yuji Kiyama 1 , Toshiya Manabe 1,2 1 Division of Neuronal Network, Institute of Medical Science, University of Tokyo, Tokyo, Japan; 2 CREST, JST, Saitama, Japan To understand molecular and cellular mechanisms of learning and memory, combinations of genetic, electrophysiological, histological and behavioral techniques have been used. We show here some examples of gene-targeted mice that exhibit learning abnormalities as well as electrophysiological and/or histological abnormalities in some areas of the limbic system such as hippocampus and amygdala. For example, we generated mice with a knockin mutation of the tyrosine (Tyr)-1472 site to phenylalanine (Y1472F) of the NR2B subunit of the NMDA receptor. The NR2B subunit is tyrosine-phosphorylated in the brain, with Tyr-1472 its major phosphorylation site. The knockin mice showed impaired fearrelated learning and reduced amygdaloid long-term potentiation. We thus identify Tyr-1472 phosphorylation as a key mediator of fear learning and amygdaloid synaptic plasticity. Research funds: KAKENHI (17023011, 18100003) and RISTEX, JST
S3A-A5 Molecular and cellular cognition: Unraveling mechanisms of learning and memory Alcino J. Silva Department of Neurobiology, UCLA, Los Angeles, USA Our laboratory is studying the role of hippocampal and prefrontal function in recent and remote memory. We are interested in uncovering general rules for how these two brain regions account for their unique roles in recent and remote memory. We are also studying how molecular mechanisms modulate cellular responses that underlie key microcircuit properties implicated in learning and memory. To accomplish this we are using a myriad of techniques including region and temporal specific transgenic manipulations, viral vectors, pharmacology, in vivo and in vitro electrophysiology, in vivo two-photon scanning confocal microscopy, as well as a battery of behavioral tasks designed to probe hippocampal and prefrontal cortical function. Our laboratory is also interested in understanding the mechanisms underlying cognitive disorders such as those underlying learning disabilities associated with Neurofibromatosis Type 1 (NF1), Tuberous Sclerosis and schizophrenia.