Inducible and Reversible NR1 Knockout Reveals Crucial Role of the NMDA Receptor in Preserving Remote Memories in the Brain

Cui, Zhenzhong; Wang, Huimin; Tan, Yi; Zaia, Kimberly A.; Zhang, Shuqin; Tsien, Joe Z.

doi:10.1016/s0896-6273(04)00072-8

Cited by 156 publications

(163 citation statements)

References 56 publications

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“…Cortical areas, such as the anterior cingulate cortex, prelimbic cortices, and the temporal cortex, have been implicated by previous genetic and pharmacological studies showing that retrieval of remote memories activates these brain regions, providing evidence that at some time point these areas become involved in memory storage (Frankland et al 2004;Maviel et al 2004). Although much has been discovered about the molecular mechanisms required for initial memory processing and synaptic consolidation, those underlying corticalrelated systems consolidation remain less well characterized (Frankland et al 2001;Cui et al 2004). Activation of cortical regions for systems consolidation appears to occur mostly during periods of inactivity and sleep (Marshall and Born 2007).…”

Section: Resultsmentioning

confidence: 99%

The impact of sleep loss on hippocampal function

2013

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Hippocampal cellular and molecular processes critical for memory consolidation are affected by the amount and quality of sleep attained. Questions remain with regard to how sleep enhances memory, what parameters of sleep after learning are optimal for memory consolidation, and what underlying hippocampal molecular players are targeted by sleep deprivation to impair memory consolidation and plasticity. In this review, we address these topics with a focus on the detrimental effects of post-learning sleep deprivation on memory consolidation. Obtaining adequate sleep is challenging in a society that values "work around the clock." Therefore, the development of interventions to combat the negative cognitive effects of sleep deprivation is key. However, there are a limited number of therapeutics that are able to enhance cognition in the face of insufficient sleep. The identification of molecular pathways implicated in the deleterious effects of sleep deprivation on memory could potentially yield new targets for the development of more effective drugs.

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Section: Resultsmentioning

confidence: 99%

The impact of sleep loss on hippocampal function

2013

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“…Instead, the evidence reviewed here suggests that spatial memory reorganizes after training like other nonspatial forms of memory and that (as with other forms of memory) the neocortex becomes gradually more important as time passes. It will be useful to pursue these issues with additional studies using pharmacological and/or genetic methods to disrupt the hippocampus reversibly during the retention interval so that spatial memory can be tested at a time when the hippocampus is "on-line" and able to support the expression of memory (Riedel et al, 1999;Cui et al, 2004;Micheau et al, 2004). Other fruitful lines of research include the use of more selective lesions (Nakazawa et al, 2002;Steffenach et al, 2002;Remondes and Schuman, 2004) and spatial tasks that do not require substantial performance demands for their expression [e.g., the "village" task (Winocur et al, 2005) and the paired-associate "event arena" (Day et al, 2003)].…”

Section: Resultsmentioning

confidence: 99%

The Hippocampus and Spatial Memory: Findings with a Novel Modification of the Water Maze

Clark¹,

Broadbent²,

Squire³

2007

Journal of Neuroscience

109

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For many tasks and species, remote memory (but not recent memory) is spared after damage to the hippocampus. An exception to this pattern of findings has been that both recent and remote memory are impaired after hippocampal lesions when rats are trained in the conventional water maze task. We explored the effect of introducing a navigational beacon for rats to use during testing. Four identical beacons were hung directly over each of the water maze quadrants, equidistant from each other (multiple-beacon maze). One of the beacons was always directly over the hidden platform. By using distal spatial cues, rats could select the correct beacon and use that beacon as a guide to the hidden platform. Probe tests indicated that rats did use the beacons to guide performance throughout training. Two months after the completion of training, rats were given hippocampal or sham lesions. Controls performed well, but the lesion group performed at chance on the retention probe trials. Furthermore, the rats with lesions not only searched indiscriminately in all four quadrants, they also did not use the beacons. These results indicate that impaired performance in the water maze after hippocampal damage reflects more than a loss of spatial information.

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“…We demonstrate here that failure in integration of dopamine signaling by the NMDA receptor in the striatum leads to behavioral consequences. Partial NR1 knockouts in which only 40-60% of the striatum neurons had NMDA receptor deletion or functional knockdown (e.g., in CaMKII, dopamine D1 receptor, or RGS9 promoter active cells that are presumably D2-positive striatal neurons) have been reported (25)(26)(27). These partial knockout mice are viable and exhibit normal locomotion in open field and basal motor function.…”

Section: Discussionmentioning

confidence: 99%

Functional disturbances in the striatum by region-specific ablation of NMDA receptors

Ohtsuka

Tansky

Kuang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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To study the role of NMDA receptors in dopamine signaling of the striatum, the brain area that receives glutamatergic inputs from various cortical areas and most dopaminergic inputs, we generated striatum-specific NMDA receptor-deficient mice. The mutant pups showed reduced food intake and retarded growth starting at the second postnatal week and died on approximately postnatal day 20 (P20). The time course of postnatal lethality is similar to that of compound mutant, double knockout of dopamine D1/D2 receptors, or genetically engineered dopamine-deficient mouse. In vivo electrophysiological recordings in the mutant pups showed that frequencies in the range of gamma oscillation were reduced in the striatal circuits. Moreover, the number of functional dopamine receptors in the striatum as measured by D1-and D2-binding experiments was greatly diminished in the mutants as compared with control animals. A consequence of diminished dopamine binding in the striatum manifested in an increase of locomotor activity. The administration of D1/D2 agonists paradoxically reduced the hyperactivity of the mutant mice as compared with an increase in locomotor activity in control mice. These results demonstrate that the NMDA receptor plays an essential role in the integration of dopamine signaling in the striatum and that is required in behavioral function.T he striatum receives glutamatergic projections from virtually all areas of the cerebral cortex and dense dopaminergic projections from the substantia nigra and ventral tegmental area (1, 2). The principal neurons of the striatum, medium spiny neurons (MSNs), are GABAergic projection neurons. These neurons are classified into two groups: the MSNs that express D1 dopamine receptors responsible for a direct pathway and the MSNs that express D2 dopamine receptors responsible for an indirect pathway (3). These MSNs constitute 90-95% of the striatal neuronal population (4) and contain high levels of NMDA receptors (5, 6).During development, dopamine receptor expressions (both D1 and D2) are already abundant by the late embryonic stage, however functional dopamine receptor binding is low at birth and progressively increases to reach adult levels between postnatal day (P)14 and P21 (7). This delayed appearance of functional dopamine receptors in the MSNs of the striatum suggests that maturation of functional dopamine receptors is regulated by an unknown mechanism, other than the mere availability of the dopamine receptor mRNAs.During postnatal weeks, it has been shown that the NMDA receptor-mediated currents develop later in the MSNs compared with other brain regions such as the hippocampus. There is a Ϸ2-fold increase from the first to the third postnatal week (8). Recently, molecular interactions between NMDA receptors and dopamine receptors have been reported. For example, NMDA receptors trap diffusible D1 receptors by direct physical interaction (9-11). The interaction between NR2B, a subunit of the NMDA receptor, and the D2 receptor can also disrupt the association of Ca 2ϩ /cal...

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Inducible and Reversible NR1 Knockout Reveals Crucial Role of the NMDA Receptor in Preserving Remote Memories in the Brain

Cited by 156 publications

References 56 publications

The impact of sleep loss on hippocampal function

The impact of sleep loss on hippocampal function

The Hippocampus and Spatial Memory: Findings with a Novel Modification of the Water Maze

Functional disturbances in the striatum by region-specific ablation of NMDA receptors

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