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    • Accordingly it is tempting to speculate that the maintenance

    2021-10-21

    Accordingly, it is tempting to speculate that the maintenance of a stimulus representation in the A2 state for a short period of time after the presentation of a specific stimulus (i.e. self-generated priming) may rely upon GluR-A-dependent synaptic plasticity. If this were the case, GluR-A Ki16425 would increase the rate at which elements of a cue presented recently decay into an inactive state (I) from the A2 state. One consequence of this processing deficit is that performance elicited by A2 processing will be impaired in GluR-A−/− mice (e.g. as in spontaneous and rewarded alternation). Whether GluR-A receptors also contribute to the maintenance of associatively primed elements in the A2 state remains an issue for further investigation. However, it is worth noting that GluR-A−/− mice show normal acquisition of conditioned responding in several standard associative learning tasks (Mead and Stephens, 2003; Johnson et al., 2005), and in spatial reference memory tasks (Reisel et al., 2002; Schmitt et al., 2003). This could be taken as evidence that associative learning and retrieval-generated priming are independent of GluR-A receptor function, at least under some conditions. Although this account is in its infancy it offers several predictions. For example, it makes the novel prediction that short-term habituation will be impaired in GluR-A−/− mice but that these mice will nevertheless show evidence of long-term habituation. This prediction is currently being investigated.
    Conclusions In summary, we have found that GluR-A receptors play a distinctive role in a specific subset of hippocampal-dependent information processing mechanisms. The finding that GluR-A deletion impairs spatial working memory whilst sparing spatial reference memory demonstrates that whilst these two types of learning are both dependent on the hippocampus, they are independent of each other at the molecular level. One possible account of this dissociation is that deficits in spatial working memory reflect impairments in specific short-term memory processes, and that associative learning (including spatial reference memory acquisition) is supported by a parallel, GluR-A-independent, mechanism. The role of GluR-A-dependent synaptic plasticity may therefore be to maintain the representation of a stimulus in a memory state that renders it less surprising if it is subsequently presented a second time (self-generated priming). The role that GluR-A plays in other forms of priming, such as retrieval-generated priming and hippocampus-dependent occasion-setting, requires further investigation (Schmitt et al., 2004a). Finally, it has been shown that increases in synaptic efficacy following LTP induction involve the rapid insertion of GluR-A-containing AMPARs into the post-synaptic membrane, and that these receptors are then gradually and continually replaced by GluR-B/GluR-C-containing AMPARs (see Malinow and Malenka, 2002, for review). This could very reasonably be taken to imply that hippocampal memory depends on a strictly serial storage process, in which GluR-B/GluR-C containing AMPARs could only support lasting memory formation following the prior establishment of changes in synaptic weights involving GluR-A-containing AMPARs. The observation that a profound spatial working memory deficit does not induce any difficulty in spatial reference memory acquisition in GluR-A−/− mice clearly contradicts such a hypothesis. It thus seems that these different memory systems must be capable, at least in principle, of functioning in parallel rather than having to function in series.
    Results and Discussion
    Supplementary data
    Acknowledgements
    Introduction The distribution of the electrostatic potential across the pore of an ion channel is critical to ion permeation and channel block mechanisms (Hille, 2001). This potential depends on numerous channel properties including local factors such as the molecular identity of side chains and global factors like pore geometry. Because the structure of the pore undergoes significant transformations during channel opening/closure, the distribution of the electrostatic potential across the pore can be state dependent. In the acetylcholine receptor channel, for example, a local ∼200-mV change in the electrostatic potential caused by a ring of glutamate residues in the open state is nearly absent in the closed state (Pascual and Karlin, 1998, Wilson et al., 2000). Similarly, in bacterial K+ channels with the intracellular gate at the crossing point of the TM2 helices in the closed conformation (KcsA), the electrostatic potential changes fairly uniformly across the entire channel pore, whereas when it is in the open conformation (MthK), the potential becomes concentrated across the narrow region of the selectivity filter (Jiang et al., 2002).