Key Points
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As a main component of the medial temporal lobe, the hippocampus has been shown to be crucial for the formation of declarative memory in humans. In rodents, the hippocampus has several features that facilitate a multilevel analysis of its function: it is required for spatial learning, which can be directly assessed with tasks such as the Morris water maze task; it demonstrates changes in synaptic efficacy, such long-term potentiation (LTP), after high-frequency input; and individual hippocampal pyramidal cells fire in a place-specific manner as an animal moves through an environment, allowing direct observation of the quality of spatial encoding.
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The N-methyl-D-aspartate receptor (NMDAR), which is highly expressed in the hippocampus, has been identified as an ideal molecular coincidence detector owing to its voltage-dependent magnesium block, high calcium permeability and slow activation and deactivation kinetics. The demonstration that the induction of hippocampal LTP depends on the activation of NMDARs further strengthened the link between LTP and Hebb's synaptic hypothesis for memory storage, in which modifications of synaptic efficacy by coincident input was the central theme
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Both pharmacological and genetic approaches have shown that hippocampal NMDARs, particularly in region CA1, are required for the acquisition of spatial memories. Furthermore, deletion of NMDARs specifically in CA1 pyramidal cells leads to a loss of the coordinated activity of CA1 place cells, with overlapping fields and a disruption of the ensemble code for space.
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NMDAR-mediated plasticity in the recurrent connections in area CA3 of the hippocampus is crucial for the rapid encoding of novel experiences, in a process that might be akin to episodic memory formation in humans. CA3-NR1-knockout mice are deficient in acquiring novel place/reward location information, and CA1 place cells in these mice were significantly impaired when recorded in a novel environment (with enlarged place fields and an augmented integrated firing rate).
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Memory retrieval is an associative process that might involve recurrent network activation as a means of pattern completion — the recall of an entire memory based on exposure to a partial set of cues. A loss of synaptic plasticity in the recurrent collaterals of area CA3 prevents this form of memory retrieval, as assessed by a spatial learning task in CA3-NR1-knockout mice, and is manifested as uncoordinated, spatially less-tuned CA1 place-cell activity under partial-cue conditions.
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Hippocampal place cells can be viewed as memory traces at the neuronal ensemble level, showing stable patterns of firing that can develop quickly and can be reactivated independently of behaviour. CA3-NR1-knockout mice have allowed the direct observation of a fourth important property of a putative memory trace — the experience-dependent formation of the spatial specificity of the fields.
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Progress has been made in understanding the part that NMDARs play in hippocampal memory, both generally, and specifically in terms of where (which subfield/cell type) and when (which phase of memory) the receptors are needed. Furthermore, the development of genetic techniques, including inducible and reversible cell-type-specific gene activation, and the establishment of more refined behavioural and physiological analyses will lead to even deeper comprehension of the relationship between plasticity, memory and space in the hippocampus.
Abstract
N-methyl-D-aspartate receptors (NMDARs) in the rodent hippocampus have been shown to be essential for spatial learning and memory, and for the induction of long-term synaptic plasticity at various hippocampal synapses. In this review, we examine the evidence concerning the role of NMDARs in hippocampal memory processes, with an emphasis on the function of NMDARs in area CA1 of the hippocampus in memory acquisition, and the unique role of NMDARs in area CA3 in the rapid acquisition and associative retrieval of spatial information. Finally, we discuss the data that have emerged from in vivo hippocampal recording studies that indicate that the activity of hippocampal place cells during behaviour is an expression of a memory trace.
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Acknowledgements
This work was supported by an individual NIH grant to S.T. and an NIH Silvio O. Conte Center grant to S.T. and M.A.W., and by grants from the Howard Hughes Medical Institute to S.T. and from the RIKEN-MIT Neuroscience Research Center to S.T. and M.A.W.
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Glossary
- FEAR CONDITIONING
-
A form of Pavlovian (classical) conditioning in which the animal learns that an innocuous stimulus (for example, an auditory tone — the conditioned stimulus or CS), reliably predicts the occurrence of a noxious stimulus (for example, foot shock — the unconditioned stimulus or US) following their repeated paired presentation. As a result of this procedure, presentation of the CS alone elicits conditioned fear responses previously associated with the noxious stimulus only.
- TRANSVERSE PATTERN LEARNING
-
A task in which animals must encode overlapping relationships between cues. A typical stimulus set is A+B−; B+C−; C+A−, where + signifies which cue is rewarded in each configuration.
- STEP-DOWN INHIBITORY AVOIDANCE TASK
-
A form of conditioning in which a rat is placed on a platform and receives a shock when it steps off the platform. Memory for the shock is measured as an increased latency to step off the platform on subsequent trials.
- PAIRED-ASSOCIATE TASK
-
A task that involves the arbitrary association of two stimuli (such as word pairs in humans, or a place and an odour or food item in animals). After exposure to the pair, the subject is presented with one stimulus and tested for recall of the second. It can be used to test declarative memory in humans, or 'episodic-like' memory in animals.
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Nakazawa, K., McHugh, T., Wilson, M. et al. NMDA receptors, place cells and hippocampal spatial memory. Nat Rev Neurosci 5, 361–372 (2004). https://doi.org/10.1038/nrn1385
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DOI: https://doi.org/10.1038/nrn1385
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