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

Scientists studied mice with a genetic mutation that causes ADNP syndrome, which is linked to autism and intellectual disability. These mice had trouble with flexible thinking, learning, memory, and social behavior. The researchers found specific brain changes that might explain these difficulties, including overactivity of certain brain proteins. Importantly, they discovered that blocking one of these overactive proteins could help fix some brain function problems, which might point to future treatments.

This preclinical study examined mouse models of ADNP syndrome, a genetic condition associated with autism spectrum disorders. Researchers found that mice with ADNP gene mutations (Adnp-HT mice) displayed cognitive inflexibility, impaired contextual learning and memory, and social deficits. The study identified specific brain changes including hyperactivity of the CaMKIIα protein and its substrates, as well as excessive long-term potentiation (a form of synaptic plasticity) in the hippocampus. Importantly, these deficits persisted into adulthood despite ADNP protein levels dropping to approximately 10% of newborn levels during juvenile development.

CaMKIIα inhibition was able to normalize the excessive long-term potentiation, suggesting a potential therapeutic target.

The identification of CaMKIIα hyperactivity as a mechanism underlying cognitive inflexibility in ADNP syndrome provides a potential therapeutic target. However, translation from mouse models to human treatments requires significant additional research. The findings may inform future drug development strategies for addressing cognitive and learning difficulties in individuals with ADNP syndrome.

This is a preclinical animal study using mouse models, which may not fully translate to human ADNP syndrome. Sample size is not reported, limiting assessment of statistical power. The study focuses primarily on hippocampal changes and may not capture the full spectrum of brain alterations in ADNP syndrome.

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.