To investigate the role of phosphatidylinositol 3 kinase (PI3 kinase) in hippocampal synaptic pla... more To investigate the role of phosphatidylinositol 3 kinase (PI3 kinase) in hippocampal synaptic plasticity, we used whole-cell patch clamp recordings from rat CA1 neurons to determine the effects of PI3 kinase inhibitors on long-term depression (LTD). PI3 kinase blockade caused a loss of synapse specificity of LTD that was dependent on the co-activation of NMDA-type glutamate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), and involved release of Ca(2+) from intracellular stores. These findings suggest that the synapse specificity of hippocampal LTD may not be an intrinsic property of this form of homosynaptic plasticity, but rather that it can be regulated by PI3 kinase.
Philosophical transactions of the Royal Society of London. Series B, Biological sciences, Jan 5, 2014
N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studi... more N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studied since it is believed to use the same molecular mechanisms that are required for many forms of learning and memory. Unfortunately, many controversies exist, not least the seemingly simple issue concerning the locus of expression of LTP. Here, we review our recent work and some of the extensive literature on this topic and present new data that collectively suggest that LTP can be explained, during its first few hours, by the coexistence of at least three mechanistically distinct processes that are all triggered by the synaptic activation of NMDARs.
Philosophical transactions of the Royal Society of London. Series B, Biological sciences, Jan 5, 2014
The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and h... more The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro, an effect that was replicated by RNAi knockdown of tau in vitro. We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.
L-Glutamate, the principal excitatory neurotransmitter in the vertebrate central nervous system, ... more L-Glutamate, the principal excitatory neurotransmitter in the vertebrate central nervous system, acts on three classes of ionotropic glutamate receptors, named after the agonists AMPA, NMDA and kainate. AMPA receptors are known to mediate fast synaptic responses and NMDA receptors to mediate slow synaptic responses at most excitatory synapses in the brain. Kainate receptors are formed from a separate set of
The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogene... more The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer's disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca(2+) and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca(2+)-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.
It is currently unknown why glutamatergic presynaptic terminals express multiple types of glutama... more It is currently unknown why glutamatergic presynaptic terminals express multiple types of glutamate receptors. We have addressed this question by studying both acute and long-term regulation of mossy fibre function in the hippocampus. We find that inhibition of both mGlu₁ and mGlu₅ receptors together can block the induction of mossy fibre LTP. Furthermore, mossy fibre LTP can be induced by the pharmacological activation of either mGlu₁ or mGlu₅ receptors, provided that kainate receptors are also stimulated. Like conventional mossy fibre LTP, chemically-induced mossy fibre LTP (chem-LTPm) depends on Ca²⁺ release from intracellular stores and the activation of PKA. Similar synergistic interactions between mGlu receptors and kainate receptors were observed at the level of Ca²⁺ signalling in individual giant mossy fibre boutons. Thus three distinct glutamate receptors interact, in both an AND and OR gate fashion, to regulate both immediate and long-term presynaptic function in the brain.
The glutamate receptor subtypes AMPA and kainate are involved in synaptic transmission and synapt... more The glutamate receptor subtypes AMPA and kainate are involved in synaptic transmission and synaptic plasticity in the CNS. Recently there has been considerable interest in understanding the molecular regulation of these receptors by proteins that directly bind to AMPA and kainate receptor subunits. Amongst the first interaction partners to be discovered were NSF, ABP, GRIP and PICK1, which bind the AMPA receptor subunit GLUA2. We have studied the functional roles of the interactions of these proteins in regulating AMPA receptor-mediated synaptic transmission and synaptic plasticity in the hippocampus. We have also started to investigate the functions of PICK1 and GRIP on kainate receptor-mediated synaptic transmission in this region. In this article we reflect upon this work, which has led to some new ideas about how AMPA and kainate receptors are regulated at synapses.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2001
To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice ... more To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice lacking this metabotropic receptor subtype (mGluR7(-/-)). After the serendipitous discovery of a sensory stimulus-evoked epileptic phenotype, we tested two convulsant drugs, pentylenetetrazole (PTZ) and bicuculline. In animals aged 12 weeks and older, subthreshold doses of these drugs induced seizures in mGluR7(-/-), but not in mGluR7(+/-), mice. PTZ-induced seizures were inhibited by three standard anticonvulsant drugs, but not by the group III selective mGluR agonist (R,S)-4-phosphonophenylglycine (PPG). Consistent with the lack of signs of epileptic activity in the absence of specific stimuli, mGluR7(-/-) mice showed no major changes in synaptic properties in two slice preparations. However, slightly increased excitability was evident in hippocampal slices. In addition, there was slower recovery from frequency facilitation in cortical slices, suggesting a role for mGluR7 as a frequenc...
The principal excitatory neurotransmitter in the vertebrate central nervous system, L-glutamate, ... more The principal excitatory neurotransmitter in the vertebrate central nervous system, L-glutamate, acts on three classes of ionotripic glutamate receptors, named after the agonists AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxalole-4-propionic acid), NMDA (N-methyl-D-aspartate) and kainate. The development of selective pharmacological agents has led to a detailed understanding of the physiological and pathological roles of AMPA and NMDA receptors. In contrast, the lack of selective kainate receptor ligands has greatly hindered progress in understanding the roles of kainate receptors. Here we describe the effects of a potent and selective agonist, ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid) and a selective antagonist, LY294486 ((3SR, 4aRS, 6SR, 8aRS)-6-((((1H-tetrazol-5-yl) methyl)oxy)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic acid), of the GluR5 subtype of kainate receptor. We have used these agents to show that kainate recept...
Pharmacological studies of long-term potentiation (LTP) in the hippocampus are starting to provid... more Pharmacological studies of long-term potentiation (LTP) in the hippocampus are starting to provide a molecular understanding of synaptic plastic processes which are believed to be important for learning and memory in vertebrates. In the CA1 region of the hippocampus, the synaptic activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype is necessary for the induction of LTP under most experimental conditions. The synaptic activation of metabotropic glutamate receptors (mGluRs) is also needed for the induction of LTP. We now show that the role of mGluRs in the induction of LTP is fundamentally different from that of NMDA receptors. NMDA receptors initiate a molecular event that needs to be triggered each time a tetanus is delivered to induce LTP. In contrast, mGluRs activate a molecular switch which then negates the need for mGluR stimulation during the induction of LTP. This mGluR-activated switch is input-specific and can be turned off by a train of low-frequency...
1. Intracellular recording techniques were used to characterize monosynaptic inhibitory postsynap... more 1. Intracellular recording techniques were used to characterize monosynaptic inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in rat hippocampal slices and to study the mechanism of paired-pulse depression of these synaptic responses. This was achieved by stimulation in stratum radiatum close (less than 0.5 mm) to an intracellularly recorded CA1 neurone after pharmacological blockade of all excitatory synaptic transmission. 2. Under these conditions, low-frequency stimulation (0.033 Hz) evoked a pure biphasic IPSP, which had a short and constant latency to onset. This IPSP was blocked by tetrodotoxin (1 microM) suggesting that it resulted from the electrical stimulation of the axons and/or cell bodies of a monosynaptic inhibitory pathway. 3. Picrotoxin (100 microM) abolished the early component of the biphasic IPSP/C. It left an intact, pure late IPSP/C (IPSP/CB) which had a latency to onset of 29 +/- 2 ms, latency to peak of 139 +/- 4 ms, a duration of 723 +/- 135 (r...
To investigate the role of phosphatidylinositol 3 kinase (PI3 kinase) in hippocampal synaptic pla... more To investigate the role of phosphatidylinositol 3 kinase (PI3 kinase) in hippocampal synaptic plasticity, we used whole-cell patch clamp recordings from rat CA1 neurons to determine the effects of PI3 kinase inhibitors on long-term depression (LTD). PI3 kinase blockade caused a loss of synapse specificity of LTD that was dependent on the co-activation of NMDA-type glutamate receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), and involved release of Ca(2+) from intracellular stores. These findings suggest that the synapse specificity of hippocampal LTD may not be an intrinsic property of this form of homosynaptic plasticity, but rather that it can be regulated by PI3 kinase.
Philosophical transactions of the Royal Society of London. Series B, Biological sciences, Jan 5, 2014
N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studi... more N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) is extensively studied since it is believed to use the same molecular mechanisms that are required for many forms of learning and memory. Unfortunately, many controversies exist, not least the seemingly simple issue concerning the locus of expression of LTP. Here, we review our recent work and some of the extensive literature on this topic and present new data that collectively suggest that LTP can be explained, during its first few hours, by the coexistence of at least three mechanistically distinct processes that are all triggered by the synaptic activation of NMDARs.
Philosophical transactions of the Royal Society of London. Series B, Biological sciences, Jan 5, 2014
The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and h... more The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro, an effect that was replicated by RNAi knockdown of tau in vitro. We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.
L-Glutamate, the principal excitatory neurotransmitter in the vertebrate central nervous system, ... more L-Glutamate, the principal excitatory neurotransmitter in the vertebrate central nervous system, acts on three classes of ionotropic glutamate receptors, named after the agonists AMPA, NMDA and kainate. AMPA receptors are known to mediate fast synaptic responses and NMDA receptors to mediate slow synaptic responses at most excitatory synapses in the brain. Kainate receptors are formed from a separate set of
The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogene... more The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer's disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca(2+) and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca(2+)-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.
It is currently unknown why glutamatergic presynaptic terminals express multiple types of glutama... more It is currently unknown why glutamatergic presynaptic terminals express multiple types of glutamate receptors. We have addressed this question by studying both acute and long-term regulation of mossy fibre function in the hippocampus. We find that inhibition of both mGlu₁ and mGlu₅ receptors together can block the induction of mossy fibre LTP. Furthermore, mossy fibre LTP can be induced by the pharmacological activation of either mGlu₁ or mGlu₅ receptors, provided that kainate receptors are also stimulated. Like conventional mossy fibre LTP, chemically-induced mossy fibre LTP (chem-LTPm) depends on Ca²⁺ release from intracellular stores and the activation of PKA. Similar synergistic interactions between mGlu receptors and kainate receptors were observed at the level of Ca²⁺ signalling in individual giant mossy fibre boutons. Thus three distinct glutamate receptors interact, in both an AND and OR gate fashion, to regulate both immediate and long-term presynaptic function in the brain.
The glutamate receptor subtypes AMPA and kainate are involved in synaptic transmission and synapt... more The glutamate receptor subtypes AMPA and kainate are involved in synaptic transmission and synaptic plasticity in the CNS. Recently there has been considerable interest in understanding the molecular regulation of these receptors by proteins that directly bind to AMPA and kainate receptor subunits. Amongst the first interaction partners to be discovered were NSF, ABP, GRIP and PICK1, which bind the AMPA receptor subunit GLUA2. We have studied the functional roles of the interactions of these proteins in regulating AMPA receptor-mediated synaptic transmission and synaptic plasticity in the hippocampus. We have also started to investigate the functions of PICK1 and GRIP on kainate receptor-mediated synaptic transmission in this region. In this article we reflect upon this work, which has led to some new ideas about how AMPA and kainate receptors are regulated at synapses.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2001
To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice ... more To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice lacking this metabotropic receptor subtype (mGluR7(-/-)). After the serendipitous discovery of a sensory stimulus-evoked epileptic phenotype, we tested two convulsant drugs, pentylenetetrazole (PTZ) and bicuculline. In animals aged 12 weeks and older, subthreshold doses of these drugs induced seizures in mGluR7(-/-), but not in mGluR7(+/-), mice. PTZ-induced seizures were inhibited by three standard anticonvulsant drugs, but not by the group III selective mGluR agonist (R,S)-4-phosphonophenylglycine (PPG). Consistent with the lack of signs of epileptic activity in the absence of specific stimuli, mGluR7(-/-) mice showed no major changes in synaptic properties in two slice preparations. However, slightly increased excitability was evident in hippocampal slices. In addition, there was slower recovery from frequency facilitation in cortical slices, suggesting a role for mGluR7 as a frequenc...
The principal excitatory neurotransmitter in the vertebrate central nervous system, L-glutamate, ... more The principal excitatory neurotransmitter in the vertebrate central nervous system, L-glutamate, acts on three classes of ionotripic glutamate receptors, named after the agonists AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxalole-4-propionic acid), NMDA (N-methyl-D-aspartate) and kainate. The development of selective pharmacological agents has led to a detailed understanding of the physiological and pathological roles of AMPA and NMDA receptors. In contrast, the lack of selective kainate receptor ligands has greatly hindered progress in understanding the roles of kainate receptors. Here we describe the effects of a potent and selective agonist, ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid) and a selective antagonist, LY294486 ((3SR, 4aRS, 6SR, 8aRS)-6-((((1H-tetrazol-5-yl) methyl)oxy)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic acid), of the GluR5 subtype of kainate receptor. We have used these agents to show that kainate recept...
Pharmacological studies of long-term potentiation (LTP) in the hippocampus are starting to provid... more Pharmacological studies of long-term potentiation (LTP) in the hippocampus are starting to provide a molecular understanding of synaptic plastic processes which are believed to be important for learning and memory in vertebrates. In the CA1 region of the hippocampus, the synaptic activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype is necessary for the induction of LTP under most experimental conditions. The synaptic activation of metabotropic glutamate receptors (mGluRs) is also needed for the induction of LTP. We now show that the role of mGluRs in the induction of LTP is fundamentally different from that of NMDA receptors. NMDA receptors initiate a molecular event that needs to be triggered each time a tetanus is delivered to induce LTP. In contrast, mGluRs activate a molecular switch which then negates the need for mGluR stimulation during the induction of LTP. This mGluR-activated switch is input-specific and can be turned off by a train of low-frequency...
1. Intracellular recording techniques were used to characterize monosynaptic inhibitory postsynap... more 1. Intracellular recording techniques were used to characterize monosynaptic inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in rat hippocampal slices and to study the mechanism of paired-pulse depression of these synaptic responses. This was achieved by stimulation in stratum radiatum close (less than 0.5 mm) to an intracellularly recorded CA1 neurone after pharmacological blockade of all excitatory synaptic transmission. 2. Under these conditions, low-frequency stimulation (0.033 Hz) evoked a pure biphasic IPSP, which had a short and constant latency to onset. This IPSP was blocked by tetrodotoxin (1 microM) suggesting that it resulted from the electrical stimulation of the axons and/or cell bodies of a monosynaptic inhibitory pathway. 3. Picrotoxin (100 microM) abolished the early component of the biphasic IPSP/C. It left an intact, pure late IPSP/C (IPSP/CB) which had a latency to onset of 29 +/- 2 ms, latency to peak of 139 +/- 4 ms, a duration of 723 +/- 135 (r...
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Papers by Graham Collingridge