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  • Hippocampal lesioned mice were less able to withhold respond


    Hippocampal-lesioned mice were less able to withhold responding during a DRL-10 requirement (i.e. when the animals had to wait 10s between lever presses), and were thus less efficient than sham operated controls. In contrast, GluR-A−/− mice did not differ from wild-type mice when the DRL requirement was 10s. However, they were significantly impaired when the DRL requirement was increased to 15s. This result was similar to that previously observed with D-AP5-treated rats (Tonkiss et al., 1988). Animals receiving the competitive NMDAR antagonist displayed a robust impairment, although the deficit was also less pronounced than that seen in rats with hippocampal lesions (Sinden et al., 1986; Tonkiss et al., 1988). GluR-A−/− mice therefore display impairments on both spatial and non-spatial tasks which require a rapid, flexible memory system that enables the animal to select between potentially equally valid behavioural options (or response alternatives) that have previously each been associated with reward and non-reward.
    NMDA receptors, LTP and spatial memory Our work with GluR-A−/− mice has therefore established a specific role for a GluR-A-dependent form of synaptic plasticity in a particular aspect of hippocampal-dependent information processing. The demonstration that it was still possible to induce some LTP in these GluR-A−/− mice, using a theta-burst stimulation paradigm, Glucose Uptake Fluorometric Assay Kit receptor open the possibility that GluR-A-independent forms of synaptic plasticity may be sufficient to support other aspects of hippocampal information processing, such as acquisition of spatial reference memory tasks (Hoffman et al., 2002). In this regard, it is worth pointing out that the residual, GluR-A-independent LTP observed in GluR-A−/− mice, was blocked by the NMDAR antagonist, D-AP5 (Hoffman et al., 2002). This of course might suggest that if the residual synaptic plasticity does underlie performance on spatial reference memory tasks, then that performance should be sensitive to manipulations of NMDAR function. The precise contribution that NMDARs make to spatial memory is still a matter of debate (see Bannerman et al., 2006, for discussion). Traditionally, this issue has been explored using pharmacological approaches. In a seminal study, Morris et al. (1986a) showed that experimentally naïve rats receiving chronic intra-cerebroventricular infusion of the NMDAR antagonist, D-AP5, were impaired in acquiring the standard spatial reference memory watermaze task. However, subsequent studies have shown that if the rats are given watermaze pre-training as normal animals, prior to being tested with NMDA antagonists in a novel spatial environment, then the drug-treated animals are in fact perfectly capable of acquiring the spatial reference memory task (Bannerman et al., 1995; Saucier and Cain, 1995). This suggests that NMDARs are not required to form a spatial representation of the environment to incrementally form an association between a particular spatial location and a goal (e.g. obtain a food reward or escape from water), or to use the spatial representation to navigate from a variable start location to a fixed location, hidden escape platform. In contrast, a role for NMDARs in hippocampus-dependent, spatial working memory tasks has been well supported by pharmacological studies. There are reports of spatial working memory deficits with AP5 on a number of tasks (Caramanos and Shapiro, 1994; Lee and Kesner, 2002; Day et al., 2003; Bast et al., 2005). For example, D-AP5-treated rats are impaired on the spatial, delayed non-matching to position (rewarded alternation) task on the elevated T-maze, the same task on which we see such a striking deficit in the GluR-A−/− mice (Tonkiss and Rawlins, 1991). D-AP5 also impairs performance on a spatial working memory, matching to place version of the watermaze task in which the platform moves to a novel position on each day of testing (Steele and Morris, 1999).
    NMDAR mutants and spatial memory