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<p>Intellectual disability (ID) is a neurodevelopmental disorder (NDD) characterized by impairments in intellectual and adaptive functioning, and is highly co-morbid with other NDDs. Recently, de novo missense variants in the gene, <i>CAMK2A</i>, which encodes calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), an abundant neuronal protein crucial for synaptic plasticity, learning and memory, have been implicated in ID. However, the causative impact of these mutations remains underexplored. In this study, we developed a heterozygous knock-in mouse model carrying the most prevalent ID-associated <i>CAMK2A</i> de novo missense variant, P212L, as a gain-of-function allele. The knock-in mice exhibited increased autophosphorylation of CaMKIIα, indicative of exuberant kinase activity, and consistently showed dendritic spine abnormalities and exaggerated hippocampal long-term potentiation induced by a subthreshold low-frequency stimulation. Furthermore, a comprehensive behavioral evaluation, including learning and memory tasks, revealed prominent phenotypes recapitulating the complex clinical phenotypes of humans with ID/NDDs harboring the same variant. Taken together, we propose that aberrant enhancement of CaMKIIα signaling by the heterozygous P212L mutation underlies a subset of ID/NDD features. These findings provide new insights into the pathogenesis of ID/NDDs, specifically through the genetic up-shifting of the critical memory regulator, CaMKII. Additionally, the established mouse model, with both construct and face validity, is expected to significantly contribute to the understanding and future therapeutic development of ID/NDDs.</p>

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A hyper-activatable CAMK2A variant associated with intellectual disability causes exaggerated long-term potentiation and learning impairments

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月26日

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  • Miao Pan,
  • Pin-Wu Liu,
  • Yukihiro Ozawa,
  • Fumiko Arima-Yoshida,
  • Geyao Dong,
  • Masahito Sawahata,
  • Daisuke Mori,
  • Masashi Nagase,
  • Hajime Fujii,
  • Shuhei Ueda,
  • Yurie Yabuuchi,
  • Xinzi Liu,
  • Hajime Narita,
  • Ayumu Konno,
  • Hirokazu Hirai,
  • Norio Ozaki,
  • Kiyofumi Yamada,
  • Hiroyuki Kidokoro,
  • Haruhiko Bito,
  • Hiroyuki Mizoguchi,
  • Ayako M. Watabe,
  • Shin-ichiro Horigane,
  • Sayaka Takemoto-Kimura

摘要

Intellectual disability (ID) is a neurodevelopmental disorder (NDD) characterized by impairments in intellectual and adaptive functioning, and is highly co-morbid with other NDDs. Recently, de novo missense variants in the gene, CAMK2A, which encodes calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), an abundant neuronal protein crucial for synaptic plasticity, learning and memory, have been implicated in ID. However, the causative impact of these mutations remains underexplored. In this study, we developed a heterozygous knock-in mouse model carrying the most prevalent ID-associated CAMK2A de novo missense variant, P212L, as a gain-of-function allele. The knock-in mice exhibited increased autophosphorylation of CaMKIIα, indicative of exuberant kinase activity, and consistently showed dendritic spine abnormalities and exaggerated hippocampal long-term potentiation induced by a subthreshold low-frequency stimulation. Furthermore, a comprehensive behavioral evaluation, including learning and memory tasks, revealed prominent phenotypes recapitulating the complex clinical phenotypes of humans with ID/NDDs harboring the same variant. Taken together, we propose that aberrant enhancement of CaMKIIα signaling by the heterozygous P212L mutation underlies a subset of ID/NDD features. These findings provide new insights into the pathogenesis of ID/NDDs, specifically through the genetic up-shifting of the critical memory regulator, CaMKII. Additionally, the established mouse model, with both construct and face validity, is expected to significantly contribute to the understanding and future therapeutic development of ID/NDDs.