Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1.

Scientists studied how certain brain proteins (Mnk1/2 kinases) affect memory and autism-like behaviors in mice. They discovered these proteins work through another protein called Syngap1, which is linked to autism in humans. When they blocked the harmful effects of these proteins, they could improve autism-like symptoms in mice. This research helps us understand how autism develops at the molecular level and may lead to new treatment approaches.

This preclinical study investigated the role of Mnk1/2 kinases in synaptic plasticity, memory, and autism-related behaviors using mouse models. Researchers found that Mnk1/2 deletion impaired memory and synaptic function, but this was independent of their known substrate eIF4E phosphorylation. The study identified Syngap1, a protein linked to syndromic autism, as a novel downstream target of Mnk1. Syngap1 knockdown reversed memory deficits in Mnk1/2 knockout mice, while pharmacological inhibition of Mnks rescued autism-related behaviors in Syngap1+/- mice.

These findings establish a Mnks-Syngap1 regulatory pathway that controls memory formation and autism-related behaviors, providing new insights into molecular mechanisms underlying autism spectrum disorders.

Identifies Mnks-Syngap1 pathway as potential therapeutic target for autism spectrum disorders. Suggests pharmacological inhibition of Mnks may improve autism-related behaviors. Provides mechanistic insights that could inform development of targeted interventions for individuals with Syngap1-related autism.

Study conducted only in mouse models with unclear sample sizes. Clinical translation to humans remains uncertain. Specific autism-related behaviors assessed not detailed in abstract. Long-term effects of interventions not reported.

MAPK interacting protein kinases 1 and 2 (Mnk1/2) regulate a plethora of functions, presumably via phosphorylation of their best characterized substrate, eukaryotic translation initiation factor 4E (eIF4E) on Ser209. Here, we show that, whereas deletion of Mnk1/2 (Mnk double knockout) impairs synaptic plasticity and memory in mice, ablation of phospho-eIF4E (Ser209) does not affect these processes, suggesting that Mnk1/2 possess additional downstream effectors in the brain. Translational profiling revealed only a small overlap between the Mnk1/2- and phospho-eIF4E(Ser209)-regulated translatome. We identified the synaptic Ras GTPase activating protein 1 (Syngap1), encoded by a syndromic autism gene, as a downstream target of Mnk1 because Syngap1 immunoprecipitated with Mnk1 and showed reduced phosphorylation (S788) in Mnk double knockout mice.

Knockdown of Syngap1 reversed memory deficits in Mnk double knockout mice and pharmacological inhibition of Mnks rescued autism-related phenotypes in Syngap1+/- mice. Thus, Syngap1 is a downstream effector of Mnk1, and the Mnks-Syngap1 axis regulates memory formation and autism-related behaviours.