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    • br The hippocampus and spatial memory Numerous

    2022-03-03


    The hippocampus and spatial memory Numerous lines of evidence have implicated the rodent hippocampus in spatial forms of learning and memory (O’Keefe and Nadel, 1978). For example, hippocampal lesions produce robust and reliable deficits on spatial memory tasks such as the Morris watermaze in both rats and mice (Morris et al., 1982, Morris et al., 1990b; Deacon et al., 2002). On the standard version of the task the animals are trained to find a hidden escape platform that remains in the same, fixed location on every trial. The rat or mouse starts from various starting points around the perimeter of the maze and has to use the extramaze cues located around the room to navigate to the platform. This version of the task is often described as a spatial reference memory task (Olton et al., 1979): the relationship between the spatial cues and the goal location, in this Cy5 azide mg case the escape platform, is the same on every trial. If, for example, the escape platform is located in the north-east quadrant of the pool for a given rat or mouse, then for that animal the correct allocentric spatial response is always to go to the north-east quadrant. Rats with hippocampal lesions are severely impaired on this task (Morris et al., 1982, Morris et al., 1990b) (see also Fig. 1, Fig. 2). In particular, the dorsal subregion of the hippocampus appears to be crucial for normal spatial memory performance (Moser et al., 1995; Bannerman et al., 1999). Mice with hippocampal lesions are equally devastated (Deacon et al., 2002; Reisel et al., 2002). Hippocampal-lesioned animals take significantly longer (in terms of both escape latencies and pathlengths) to find the platform during training (Fig. 1). In addition, a probe trial conducted at the end of training, during which the platform is removed from the pool and the rat or mouse allowed to swim freely for 60s, shows that whereas control animals will spend most of their time searching in the area of the pool where the platform was previously located, rats or mice with hippocampal lesions show no such search preference for the training quadrant (Fig. 2). If the amount of time the animals spend in the four quadrants of the pool is plotted, the control animals show a clear preference for the training quadrant in which the platform had been located, whereas animals with complete or dorsal hippocampal lesions show no such preference (chance performance is 25%).
    AMPA receptors and hippocampus-dependent spatial memory A generic role for AMPARs in hippocampus-dependent spatial learning is well established (Riedel et al., 1999). Direct intra-hippocampal infusion of the AMPAR antagonist, LY326325, given during the training phase, disrupted acquisition of the standard version of the fixed-location, hidden-platform, spatial reference memory version of the watermaze task. Similarly, the expression of previously acquired spatial information was also disrupted by AMPAR blockade. Animals that were trained on this version of the watermaze task under vehicle infusion conditions, but then subsequently received the AMPAR antagonist during the probe test to assess expression of this previously acquired spatial memory, were unable to successfully retrieve the correct platform location. This study, therefore, clearly demonstrated a role for hippocampal AMPARs in spatial memory. The contribution that different AMPAR subunits make to hippocampal function was initially limited by the lack of subunit-selective ligands. The development of genetically modified mice in which individual AMPAR subunits can be selectively deleted or modified has now opened the door, allowing the contribution that these individual proteins make to various forms of learning and memory to be studied. The AMPAR subtype of excitatory amino acid glutamate receptor is a hetero-oligomeric protein complex consisting of combinations of four different kinds of subunits (GluR-A–GluR-D; GluR1–GluR4), each encoded by a separate gene: gria 1–4 (Wisden and Seeburg, 1993). In recent years, genetically modified mice lacking each of the individual GluR subunits have been generated and their behaviour has been studied across a range of learning and memory paradigms: GluR-B (Shimshek et al., 2006); GluR-C (Sanchis-Segura et al., 2006); GluR-D (Fuchs et al., 2007). Mice lacking the GluR-A subunit of the AMPA receptor have been of particular interest (Zamanillo et al., 1999). Studies of these mice have revealed important dissociations between distinct aspects of hippocampal information processing.