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The mouse model of intellectual disability by ZBTB18/RP58 haploinsufficiency shows cognitive dysfunction with synaptic impairment

Molecular Psychiatry volume 28, pages 2370–2381 (2023)Cite this article

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Abstract

ZBTB18/RP58 (OMIM *608433) is one of the pivotal genes responsible for 1q43q44 microdeletion syndrome (OMIM #612337) and its haploinsufficiency induces intellectual disability. However, the underlying pathological mechanism of ZBTB18/RP58 haploinsufficiency is unknown. In this study, we generated ZBTB18/RP58 heterozygous mice and found that these mutant mice exhibit multiple behavioral deficits, including impairment in motor learning, working memory, and memory flexibility, which are related to behaviors in people with intellectual disabilities, and show no gross abnormalities in their cytoarchitectures but dysplasia of the corpus callosum, which has been reported in certain population of patients with ZBTB18 haploinsufficiency as well as in those with 1q43q44 microdeletion syndrome, indicating that these mutant mice are a novel model of ZBTB18/RP58 haploinsufficiency, which reflects heterozygotic ZBTB18 missense, truncating variants and some phenotypes of 1q43q44 microdeletion syndrome based on ZBTB18/RP58 haploinsufficiency. Furthermore, these mice show glutamatergic synaptic dysfunctions, including a reduced glutamate receptor expression, altered properties of NMDA receptor-mediated synaptic responses, a decreased saturation level of long-term potentiation of excitatory synaptic transmission, and distinct morphological characteristics of the thick-type spines. Therefore, these results suggest that ZBTB18/RP58 haploinsufficiency leads to impaired excitatory synaptic maturation, which in turn results in cognitive dysfunction in ZBTB18 haploinsufficiency.

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Fig. 1: RP58 expression in the brain of heterozygous RP58+/– mice.
Fig. 2: Defects in the formation of cortical callosum in RP58+/– mice.
Fig. 3: Behavioral deficits in RP58+/– mice.
Fig. 4: Disrupted glutamate receptor expression in RP58+/– mice.
Fig. 5: Altered NMDA receptor I–V curve and decreased LTP saturation level in RP58+/– mice.
Fig. 6: Dendritic spine morphology and density in the hippocampus of RP58+/– mice.

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Acknowledgements

We thank Dr. Masataka Kasai for the use of RP58 mutant mice, Dr. Minoru Saitoe for their helpful comments on the manuscript, Dr. Yoko Tsukamoto for the initial electrophysiological experiment, Dr. Shigeo Okabe for the valuable suggestions on the morphological analysis of the spines, and the members of our laboratory for their technical assistance and critical comments. This work was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Science, Sports, Culture and Technology of Japan (19K08033, 18KK0442), and Intramural Research Grant (3-1) for Neurological and Psychiatric Disorders provided by the National Center of Neurology and Psychiatry, Japan (to HM), and KAKENHI (18H02537, 18K19383, 22H02729) (to HO).

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Author notes

  1. Hideki Miwa, Hiroko Shimbo, Keisuke Nakajima & Haruo Okado

    Present address: Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan

  2. Tomoko Tanaka

    Present address: Department of Basic Medical Science, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan

  3. Chiaki Ohtaka-Maruyama

    Present address: Developmental Neuroscience Project, Department of Brain & Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

  4. Shinobu Hirai

    Present address: Brain Metabolic Regulation Group, Frontier Laboratory, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan

  5. These authors contributed equally: Sayaka Hirai, Hideki Miwa, Hiroko Shimbo.

Authors and Affiliations

  1. Neural Development Project, Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan

    Sayaka Hirai, Hideki Miwa, Hiroko Shimbo, Keisuke Nakajima, Masahiro Kondo, Tomoko Tanaka, Chiaki Ohtaka-Maruyama, Shinobu Hirai & Haruo Okado

  2. Molecular Neuropsychopharmacology Section, Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, 187-8553, Japan

    Hideki Miwa

  3. Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama, Japan

    Hiroko Shimbo

  4. Department of Legal Medicine, Nihon University School of Dentistry, Chiyoda, Tokyo, 101-8310, Japan

    Masahiro Kondo

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Contributions

Sayaka H (SaH), HM, HS, and HO. designed the research; SaH, HM, HS, KN, MK, TT, COM, Shinobu H (Sh H), and HO performed the research; SaH, HM, HS, KN, MK, TT, COM, ShH, and HO analyzed the data; SaH, HM, HS, ShH and HO prepared the paper.

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Correspondence to Hideki Miwa, Shinobu Hirai or Haruo Okado.

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Hirai, S., Miwa, H., Shimbo, H. et al. The mouse model of intellectual disability by ZBTB18/RP58 haploinsufficiency shows cognitive dysfunction with synaptic impairment. Mol Psychiatry 28, 2370–2381 (2023). https://doi.org/10.1038/s41380-023-01941-3

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