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

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 CaMKIIa 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 similar to 10% of the newborn level. The adult Adnp-HT hippocampus shows hyperphosphorylated CaMKIIa and its substrates, including SynGAP1, and excessive long-term potentiation that is normalized by CaMKIIa inhibition. Therefore, Adnp haploinsufficiency in mice leads to cognitive inflexibility involving CaMKIIa hyperphosphorylation and excessive LTP in adults long after its marked expressional decrease in juveniles.

Automated summary

ADNP syndrome, characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD), involves the ADNP transcription factor of the SWI/SNF chromatin-remodeling complex. Adnp-haploinsufficient (Adnp-HT) mice display synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIa hyperactivity. These mice show impaired contextual learning and memory, social deficits, and hyperphosphorylated CaMKIIa and its substrates in the adult hippocampus, which can be normalized by CaMKIIa inhibition.