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  • br Experimental procedures Adk tg Adktm tg UbiAdk mice

    2024-02-26


    Experimental procedures Adk-tg (Adktm1−/−:tg(UbiAdk) mice were created by breeding a loxP-flanked Adk transgene under the control of a human ubiquitin promoter into ADK knockout mice (Fedele et al., 2005,). Fb-Adk-def (Adktm1−/−:tg(UbiAdk):Emx1-Cre-tg3) mice were generated by pairing Emx1-Cre-tg3 mice, which expressed Cre-recombinase in neurons and astrocytes of the telencephalon (Iwasato et al., 2004), with Adk-tg mice (Li et al., 2008). Adk-tg and fb-Adk-def mice were obtained as littermates. Control animals were derived from a matched WT C57BL/6 background maintained in parallel as previously described (Yee et al., 2007). The regional alteration of ADK MK-8245 mg has been validated by immunohistochemistry as described before (Li et al., 2008, Shen et al., 2011). Here, we provide a new set of coronal sections taken at two different anterior–posterior levels obtained from the same animals (Fig. 1A, B) with accompanying heat-map illustrations to demonstrate: (i) The brain-wide elevated expression of ADK in the Adk-tg mice was prominent in the striatum, extending to the ventral pallidum, and the entire cortical mantle and limbic cortices including hippocampus and amygdala, with a milder increase seen in the thalamus and basal midbrain areas. (ii) The comparably prominent elevation of ADK expression seen in fb-Adk-def mice was restricted only to the striatal–pallidal structures, thalamus and mid-brain areas, but a clear deficiency relative to wild-type controls can be delineated throughout the entire cortical mantle extending from neocortical to allocortical structures including the hippocampus and the amygdala.
    Results
    Discussion Here, global adenosine deficiency following brain-wide up-regulation of ADK led to a significant impairment in spatial working memory in the Adk-tg mice without any apparent impact on spatial reference memory or spatial familiarity judgment. The latter outcomes exclude the possibility that the working memory deficiency stemmed from non-specific motor deficits, impairment in the sensory perception of spatial cues, or lack of motivation to seek food reward. By comparison, region-specific up-regulation of adenosine in the cortex and hippocampus within the Adk-tg background – as a result of telencephalon-specific disruption of the ADK transgene, exacerbated rather than ameliorated the working memory deficit associated with brain-wide over-expression of ADK in Adk-tg mice. Likewise, the hyper-responsiveness to MK-801 seen in Adk-tg mice was exacerbated by the local increase in extracellular adenosine introduced specifically to the telencephalon. Thus, the magnitude of the working memory deficit and the sensitivity to NMDAR blockade seemed to go hand in hand. Although the present study cannot ascertain the existence of a causal link between NMDAR hypofunction and working memory deficit in our mutant mice, this speculation certainly warrants serious consideration. It may be tested by assessing whether drugs that enhance NMDAR function, such as glycine transporter 1 inhibitor therapy (Singer et al., 2009), would ameliorate the memory deficits. Although their phenotypic profile was similar, the impression that Adk-tg and fb-Adk-def mice were clearly distinguishable by the severity of their phenotypic expression excluded the possibility that their common adenosine over-expression outside the MK-8245 mg telencephalon (e.g., the striatum) could be solely responsible for the phenotypes demonstrated here. Such a view would also be hard to reconcile with the consensus that blockade of striatal ARs, in particular A2ARs, has been associated with performance enhancement in working memory tests (Takahashi et al., 2008, Wei et al., 2011). Indeed, any difference in phenotypic expression between the two mutant lines must be attributable to the local Adk deletion introduced to the telencephalon that sets the two apart from each other. As will be discussed later, this is not to deny that subcortical/striatal adenosine normally may also modulate cognitive performance.