Establishments of a mouse model of intellectual disability (IMAGE)
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RP58/ZBTB18 is a transcriptional repressor protein, and the gene is located on chromosome 1. Missense or truncating variants, or deletion of RP58/ZBTB18 reduces the function of RP58, resulting in the induction of intellectual disability. To elucidate this pathology, we generated and analyzed Rp58 heterozygous deletion mice and found behavioral abnormalities resembling patients with intellectual disability. Specifically, in addition to reduced working memory, we found reduced reversal learning ability in the water maze test, suggesting reduced flexibility in cognitive memory capacity. These results can be considered to correspond to a decline in intellectual function and adaptive capacity observed in patients with intellectual disability. There are two possible reasons why these behavioral phenotypes were observed in RP58 heterozygous mice. 1. The mouse model showed abnormalities in glutamatergic signaling; when we examined long-term potentiation involving NMDA receptors, we found that there was no difference in long-term potentiation with a single frequent stimulus, but that long-term potentiation saturated at a lower rate with repeated frequent stimulation. This change in synaptic plasticity properties indicates a smaller capacity for plasticity in memory learning, suggesting that it is the basis for reduced plasticity. 2. Analysis of dendritic spine morphology revealed abnormalities in mature-type spine morphology, with smaller spine head widths and shorter spine lengths in Rp58 heterozygous mice, suggesting maturation defects in mature-type spines.
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