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    • br GluR A knockout mice Genetically

    2022-01-10


    GluR-A knockout mice Genetically modified, adult mice lacking the GluR-A AMPA receptor subunit exhibit fast synaptic transmission in the hippocampus, mediated by the receptors formed from the remaining AMPA receptor subunits GluR-B and GluR-C (Sommer et al., 1991), but are deficient in a rapidly expressed component of synaptic plasticity at CA3-to-CA1 synapses in the hippocampus (Zamanillo et al., 1999; Hoffman et al., 2002; Malinow and Malenka, 2002; Jensen et al., 2003). Behavioural studies of GluR-A knockout mice have revealed striking dissociations between different aspects of hippocampus-dependent information processing. GluR-A−/− mice, like animals with hippocampal lesions, display a robust and enduring spatial working memory deficit (Reisel et al., 2002; Schmitt et al., 2003, Schmitt et al., 2004b). Nevertheless, GluR-A−/− mice show no impairment on tests of spatial reference memory (Zamanillo et al., 1999; Reisel et al., 2002; Schmitt et al., 2003). This is in direct Itraconazole to hippocampal-lesioned rodents (Morris et al., 1982; Deacon et al., 2002; Reisel et al., 2002) and rats with a intra-hippocampal AMPAR blockade following infusion of LY326325 (Riedel et al., 1999). Taken together these results suggest that there are separate and distinct molecular mechanisms within the hippocampus supporting spatial working and reference memory.
    Spatial reference memory is GluR-A-independent In contrast to the severe impairments seen with hippocampal lesions, or complete intra-hippocampal AMPAR blockade, GluR-A knockout mice were able to acquire the spatial reference memory watermaze task as well as wild-type controls (Zamanillo et al., 1999; Reisel et al., 2002). The knockout mice had similar escape latencies and pathlengths during acquisition (Fig. 1), and the performance of the wild-type and GluR-A−/− groups on the probe trial was indistinguishable (Fig. 2). Both groups had learned to an equal extent about the location of the platform, with wild-type and knockout mice showing a strong preference for the quadrant of the pool in which the platform had been located. Similar findings have been reported for genetically modified mice in which phosphorylation sites on the GluR-A subunit have been altered. These GluR-A point mutants also display intact spatial reference memory acquisition in the watermaze (Lee et al., 2003). The observation that GluR-A knockout mice acquire spatial reference memory tasks as well as control mice was subsequently confirmed using an appetitively motivated radial maze task (Olton et al., 1979). The radial maze that we used consisted of six arms radiating out from a central platform like spokes on a wheel (Fig. 3). To assess spatial reference memory, three of the arms were baited with milk rewards and the other three were never baited. The identity of the baited and non-baited arms remained constant across all trials. Consequently the animal had to learn which arms are rewarded and which arms are never rewarded. The mice were placed on the central platform at the start of a trial and allowed to explore and enter arms until all three milk rewards had been collected. During this phase of the study animals were only allowed to enter each arm once. Once an arm had been visited, the door to that arm was closed and remained shut thereafter. Crucially, the maze was periodically rotated to prevent the mice from using intramaze cues. For this reference memory task, the spatial responses that the animals are required to make to collect the food rewards remain the same across all of the training trials. If an animal entered an arm that was never baited then that was scored as a reference memory error. Mice with hippocampal lesions were unable to acquire the spatial reference memory radial maze task (Schmitt et al., 2003) (Fig. 3). They were unable to learn which arms were baited and which arms were never baited, and continued to enter the un-rewarded arms. Indeed, even after extensive training the hippocampal-lesioned mice showed no improvement. In contrast to hippocampal-lesioned mice, but not surprisingly in view of the previous watermaze result, the GluR-A knockout mice acquired the spatial reference memory component of the three from six radial maze task just as well as the control animals (Fig. 3). The mutant mice were perfectly capable of learning to avoid the never-baited arms, and both groups of mice made equivalent numbers of reference memory errors during acquisition. This result confirmed that hippocampus-dependent spatial reference memory is GluR-A-independent. In view of the widely held belief that hippocampal long-term potentization (LTP) underlies performance on hippocampus-dependent memory tasks, this result came as something of a surprise. It also suggested that AMPARs composed of other subunits were likely to be of crucial importance for spatial reference memory performance (Shimshek et al., 2006).