NMDA receptors and memory encoding
TL;DR: How my then interest in long-term potentiation (LTP) as a model of memory enabled me to recognise the importance of Collingridge et al.'s discovery is laid out - and how the idea that NMDA receptor activation is essential for memory encoding, though not for storage, took time to develop and to be accepted.
About: This article is published in Neuropharmacology.The article was published on 2013-11-01. It has received 234 citations till now. The article focuses on the topics: Synaptic plasticity & Long-term potentiation.
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TL;DR: A review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the Accumbens can inhibit drug seeking in the laboratory setting is provided.
Abstract: The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.
408 citations
Cites background from "NMDA receptors and memory encoding"
...As discussed above, NMDARs serve as key regulators of the synaptic plasticity linked to the neurologic processes controlling learning and memory (Morris, 2013), with pharmacological blockade of NMDARs being a common mechanism of action for dissociative anesthetic drugs including ketamine and…...
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TL;DR: The relationship between NMDA receptor structure and function is reviewed with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor.
Abstract: NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor.
316 citations
Cites background from "NMDA receptors and memory encoding"
...The distinction of glycine or d-serine appears to depend on brain region in addition to the subcellular localization of the receptor (Wolosker, 2007; Oliet and Mothet, 2009; Mothet et al., 2015)....
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TL;DR: Novel molecular and functional insight is reviewed into how CaMKII supports synaptic function by reviewing the multilayered and complex nature ofCaMKII's involvement in synaptic regulation.
277 citations
Cites background from "NMDA receptors and memory encoding"
...CaMKII activation by Ca2+ influx via NMDA receptors (NMDARs) is essential for standard hippocampal LTP and hippocampusbased learning (Kerchner and Nicoll, 2008; Lisman et al., 2012; Malenka and Bear, 2004; Morris, 2013)....
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TL;DR: Hippocampal place cells take part in sequenced patterns of reactivation after behavioral experience, known as replay, and a focus on the phenomenology of replay is focused on.
Abstract: Hippocampal place cells take part in sequenced patterns of reactivation after behavioral experience, known as replay. Since replay was first reported, nearly 20 years ago, many new results have been found, necessitating revision of the original interpretations. We review some of these results with a focus on the phenomenology of replay.
261 citations
TL;DR: It is concluded that the presence of GluN2B subunit-containing NMDARs at the postsynaptic density might be a necessary, though not a sufficient, condition for the strengthening of individual synapses.
Abstract: N-Methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity is a strong candidate to mediate learning and memory processes that require the hippocampus. This plasticity is bidirectional, and how the same receptor can mediate opposite changes in synaptic weights remains a conundrum. It has been suggested that the NMDAR subunit composition could be involved. Specifically, one subunit composition of NMDARs would be responsible for the induction of long-term potentiation (LTP), whereas NMDARs with a different subunit composition would be engaged in the induction of long-term depression (LTD). Unfortunately, the results from studies that have investigated this hypothesis are contradictory, particularly in relation to LTD. Nevertheless, current evidence does suggest that the GluN2B subunit might be particularly important for plasticity and may make a synapse bidirectionally malleable. In particular, we conclude that the presence of GluN2B subunit-containing NMDARs at the postsynaptic density might be a necessary, though not a sufficient, condition for the strengthening of individual synapses. This is owing to the interaction of GluN2B with calcium/calmodulin-dependent protein kinase II (CaMKII) and is distinct from its contribution as an ion channel.
232 citations
References
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TL;DR: A model of a system having a large number of simple equivalent components, based on aspects of neurobiology but readily adapted to integrated circuits, produces a content-addressable memory which correctly yields an entire memory from any subpart of sufficient size.
Abstract: Computational properties of use of biological organisms or to the construction of computers can emerge as collective properties of systems having a large number of simple equivalent components (or neurons). The physical meaning of content-addressable memory is described by an appropriate phase space flow of the state of a system. A model of such a system is given, based on aspects of neurobiology but readily adapted to integrated circuits. The collective properties of this model produce a content-addressable memory which correctly yields an entire memory from any subpart of sufficient size. The algorithm for the time evolution of the state of the system is based on asynchronous parallel processing. Additional emergent collective properties include some capacity for generalization, familiarity recognition, categorization, error correction, and time sequence retention. The collective properties are only weakly sensitive to details of the modeling or the failure of individual devices.
16,652 citations
TL;DR: It is reported that, in addition to a spatial discrimination impairment, total hippocampal lesions also cause a profound and lasting placenavigational impairment that can be dissociated from correlated motor, motivational and reinforcement aspects of the procedure.
Abstract: Electrophysiological studies have shown that single cells in the hippocampus respond during spatial learning and exploration1–4, some firing only when animals enter specific and restricted areas of a familiar environment. Deficits in spatial learning and memory are found after lesions of the hippocampus and its extrinsic fibre connections5,6 following damage to the medial septal nucleus which successfully disrupts the hippocampal theta rhythm7, and in senescent rats which also show a correlated reduction in synaptic enhancement on the perforant path input to the hippocampus8. We now report, using a novel behavioural procedure requiring search for a hidden goal, that, in addition to a spatial discrimination impairment, total hippocampal lesions also cause a profound and lasting placenavigational impairment that can be dissociated from correlated motor, motivational and reinforcement aspects of the procedure.
6,143 citations
"NMDA receptors and memory encoding" refers background in this paper
...What emerged was a series of studies investigating the impact of D,L-AP5 (soon after we used D-AP5) on spatial learning in the watermaze (Morris et al., 1982)....
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TL;DR: Results of computer simulations of a network designed to solve a difficult but well-defined optimization problem-the Traveling-Salesman Problem-are presented and used to illustrate the computational power of the networks.
Abstract: Highly-interconnected networks of nonlinear analog neurons are shown to be extremely effective in computing. The networks can rapidly provide a collectively-computed solution (a digital output) to a problem on the basis of analog input information. The problems to be solved must be formulated in terms of desired optima, often subject to constraints. The general principles involved in constructing networks to solve specific problems are discussed. Results of computer simulations of a network designed to solve a difficult but well-defined optimization problem-the Traveling-Salesman Problem-are presented and used to illustrate the computational power of the networks. Good solutions to this problem are collectively computed within an elapsed time of only a few neural time constants. The effectiveness of the computation involves both the nonlinear analog response of the neurons and the large connectivity among them. Dedicated networks of biological or microelectronic neurons could provide the computational capabilities described for a wide class of problems having combinatorial complexity. The power and speed naturally displayed by such collective networks may contribute to the effectiveness of biological information processing.
5,328 citations
"NMDA receptors and memory encoding" refers background in this paper
...Now famous work by others, notably Hopfield and Tank, formalised the properties and learning-rule requirements of distributedassociative memories (Hopfield, 1982; Hopfield and Tank, 1985)....
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TL;DR: The voltage dependence of the NMDA receptor-linked conductance appears to be a consequence of the voltage dependenceof the Mg2+ block and its interpretation does not require the implication of an intramembrane voltage-dependent ‘gate’.
Abstract: The responses of vertebrate neurones to glutamate involve at least three receptor types. One of these, the NMDA receptor (so called because of its specific activation by N-methyl-D-aspartate), induces responses presenting a peculiar voltage sensitivity. Above resting potential, the current induced by a given dose of glutamate (or NMDA) increases when the cell is depolarized. This is contrary to what is observed at classical excitatory synapses, and recalls the properties of 'regenerative' systems like the Na+ conductance of the action potential. Indeed, recent studies of L-glutamate, L-aspartate and NMDA-induced currents have indicated that the current-voltage (I-V) relationship can show a region of 'negative conductance' and that the application of these agonists can lead to a regenerative depolarization. Furthermore, the NMDA response is greatly potentiated by reducing the extracellular Mg2+ concentration [( Mg2+]o) below the physiological level (approximately 1 mM). By analysing the responses of mouse central neurones to glutamate using the patch-clamp technique, we have now found a link between voltage sensitivity and Mg2+ sensitivity. In Mg2+-free solutions, L-glutamate, L-aspartate and NMDA open cation channels, the properties of which are voltage independent. In the presence of Mg2+, the single-channel currents measured at resting potential are chopped in bursts and the probability of opening of the channels is reduced. Both effects increase steeply with hyperpolarization, thereby accounting for the negative slope of the I-V relationship of the glutamate response. Thus, the voltage dependence of the NMDA receptor-linked conductance appears to be a consequence of the voltage dependence of the Mg2+ block and its interpretation does not require the implication of an intramembrane voltage-dependent 'gate'.
3,977 citations
"NMDA receptors and memory encoding" refers background in this paper
...…that what captured attention from the outset was the coincidence detecting function of NMDA receptors, arising from the magnesium block in the resting state and the dual ligand and voltage-dependent characteristics of the receptor (Ascher and Nowak, 1987; Mayer et al., 1984; Nowak et al., 1984)....
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TL;DR: This article showed that chronic intraventricular infusion of D,L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage, without affecting visual discrimination learning.
Abstract: Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophosphonovaleric acid (AP5) does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of hippocampal long-term potentiation (LTP) following brief high-frequency stimulation. We now report that chronic intraventricular infusion of D,L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage, without affecting visual discrimination learning, which is not. The L-isomer of AP5 did not produce behavioural effects. AP5 treatment also suppressed LTP in vivo. These results suggest that NMDA receptors are involved in spatial learning, and add support to the hypothesis that LTP is involved in some, but not all, forms of learning.
3,488 citations