Astrocytic polyamine transport by ATP13A4 tunes excitatory synaptic transmission

Polyamines, such as spermidine and spermine, are essential for brain function and neurodevelopment. These soluble molecules modulate glial and neuronal ion channels, transporters, and receptors, contributing to cellular communication in the brain. Within the brain, polyamines primarily accumulate in astrocytes, but the mechanisms of polyamine uptake in astrocytes and the physiological relevance of this process in brain function remain poorly understood. Here, we identified ATP13A4, a P5B-type transport ATPase predominantly expressed in astrocytes, as a key polyamine transporter that regulates polyamine uptake and homeostasis in astrocytes. Using primary cultures and rodent models, we show that ATP13A4 deficiency reduces astrocyte morphological complexity and increases excitatory synapse formation. Exogenous spermidine application recapitulated these effects, suggesting that astrocytes play a critical role in clearing extracellular polyamines. Moreover, we identified a novel homozygous p.E276K variant of ATP13A4 in a patient with intellectual disability and a heterozygous deletion spanning exons 19-25 in a patient with epilepsy. Additionally, we characterized two ATP13A4 variants previously associated with autism and language impairment. These variants exhibited loss-of-function phenotypes, pointing to a link between imbalanced polyamine homeostasis and neurodevelopmental disorders. Correspondingly, Atp13a4 KO mice exhibit mild, sex-specific behavioral deficits. Female KO mice display subtle changes in anxiety-like behavior, spatial learning, motor coordination, and seizure susceptibility, aligning with features observed in patients with loss-of-function ATP13A4 mutations. In summary, astrocytes take up extracellular polyamines via ATP13A4, which regulate astrocyte arborization and excitatory synapse formation, significantly impacting neurodevelopment and behavior. This work provides the first direct link between dysfunctional astrocytic polyamine transport and perturbations in brain development, providing novel insights into the molecular mechanisms underlying neurodevelopmental disorders.