In agreement with the results obtained
In agreement with the results obtained from GluR-A−/− mice, mice in which the NR1 subunit of the NMDA receptor has been selectively deleted from the CA3 subfield of the hippocampus displayed normal acquisition of the standard reference memory version of the watermaze task (Nakazawa et al., 2002), but were impaired on a spatial working memory, matching to position version (Nakazawa et al., 2003). In contrast, CA1-specific NR1 knockout mice have been reported to display poorer spatial reference memory acquisition in the watermaze (Tsien et al., 1996). It should also be noted, however, that these CA1 NR1 knockout mice were also impaired during performance of a visible platform control task (a task that does not require an intact hippocampus (Morris et al., 1986b), although by the end of training they were performing as well as the controls. This might suggest a more general disruption of watermaze performance rather than a spatial learning impairment per se, and may also suggest that the NR1 deletion may be less specific to the hippocampus than was hoped for.
NR2 subunit selective knockout mice have also been produced. Mice with unconditional deletion of the NR2B subunits die perinatally (Kutsuwada et al., 1996), but NR2A knockout mice are viable. These NR2A−/− mice have been reported to show a mild impairment in the Morris watermaze, although they clearly learned a substantial amount about the spatial location of the platform. Therefore, there are questions as to how robust and reliable this deficit actually is, and whether it generalises to other tests of spatial reference memory (Bannerman et al., 2006).
Dentate-gyrus-specific NR1 knockout selectively impairs spatial working memory We have also recently generated genetically modified mice that are deficient in the NR1 subunit of the NMDAR, specifically and exclusively within the dentate gyrus of the hippocampal formation (Niewoehner et al., 2007) (Fig. 7). Mice carrying floxed NR1 NHS-12-Biotin australia were generated and tTA-induced Cre expression was used to destroy the NR1 gene, specifically in dentate granule cells (Krestel et al., 2004) (Fig. 7A). In situ hybridization and immunohistochemical analyses revealed a selective deletion of the NR1 subunit in the dentate gyrus, whereas there was no evidence of any reduction in NR1 subunit levels in any of the other hippocampal subfields, or anywhere else in the brain (Fig. 7B, C). These NR1 mice displayed severely impaired LTP in both medial and lateral perforant path inputs to the DG, whereas LTP was unchanged in CA3-to-CA1 cell synapses in hippocampal slices. We assessed the behaviour of the NR1 mice using the same three from six radial maze task that we had previously used to characterise the GluR-A−/− mice, allowing us to investigate both spatial reference memory and spatial working memory (Schmitt et al., 2003). NR1 and wild-type mice acquired the spatial reference memory component of the radial maze task at the same rate, and both groups were able to learn to discriminate between the always-baited and never-baited arms (Fig. 7D). However, when the working memory component was introduced, the NR1 mice were less able to keep track of which arms they had already visited on a particular trial, and made significantly more spatial working memory errors than their wild-type counterparts (Fig. 7E). At the same time, however, they were still able to avoid the non-baited arms. This pattern of sparings and impairments is the same as that seen with the GluR-A−/− mice, although the magnitude of the spatial working memory impairment in the dentate-specific knockout is much smaller than that observed in the constitutive, wholebrain GluR-A knockout.
So far we have worked under the assumption that the spatial working memory phenotype in mice with a constitutive, wholebrain GluR-A deletion is hippocampal in origin. Although we have clearly demonstrated that an exclusively hippocampus-specific manipulation of LTP (the dentate gyrus-specific deletion of the NR1 subunit of the NMDAR) can give rise to a behavioural phenotype in which impaired spatial working memory co-exists with normal spatial reference memory (Nakazawa et al., 2002, Nakazawa et al., 2003; Niewoehner et al., 2007), it is of course the case that we cannot rule out the possibility that deletion of GluR-A in a brain area, or brain areas, other than the hippocampus could also contribute to the observed dissociation between impaired spatial working memory and spared spatial reference memory.