Adnp-mutant mice with cognitive inflexibility, CaMKIIα hyperactivity, and synaptic plasticity deficits.

Heejin Cho, Taesun Yoo, Heera Moon, Hyojin Kang, Yeji Yang, MinSoung Kang, Esther Yang, Dowoon Lee, Daehee Hwang, Hyun Kim, Doyoun Kim, Jin Young Kim, Eunjoon Kim

Molecular psychiatry 2023 Aug

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ADNP syndrome, involving the ADNP transcription factor of the SWI/SNF chromatin-remodeling complex, is characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD). Although Adnp-haploinsufficient (Adnp-HT) mice display various phenotypic deficits, whether these mice display abnormal synaptic functions remain poorly understood. Here, we report synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIα hyperactivity in Adnp-HT mice. These mice show impaired and inflexible contextual learning and memory, additional to social deficits, long after the juvenile-stage decrease of ADNP protein levels to ~10% of the newborn level. The adult Adnp-HT hippocampus shows hyperphosphorylated CaMKIIα and its substrates, including SynGAP1, and excessive long-term potentiation that is normalized by CaMKIIα inhibition. Therefore, Adnp haploinsufficiency in mice leads to cognitive inflexibility involving CaMKIIα hyperphosphorylation and excessive LTP in adults long after its marked expressional decrease in juveniles. © 2023. The Author(s).

Citation

Heejin Cho, Taesun Yoo, Heera Moon, Hyojin Kang, Yeji Yang, MinSoung Kang, Esther Yang, Dowoon Lee, Daehee Hwang, Hyun Kim, Doyoun Kim, Jin Young Kim, Eunjoon Kim. Adnp-mutant mice with cognitive inflexibility, CaMKIIα hyperactivity, and synaptic plasticity deficits. Molecular psychiatry. 2023 Aug;28(8):3548-3562