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. 

The authors have declared no competing interest.

This work was funded by the Fonds voor Wetenschappelijk Onderzoek (FWO, Research Foundation Flanders) (G094219N to P.V., G011424N to P.V. and S.v.V.), the Queen Elisabeth Medical Foundation for Neurosciences (to S.v.V.) and Aligning Science Across Parkinson′s (ASAP-000458 to P.V. and V.B.; and ASAP-020607 to C.E.) through the Michael J. Fox Foundation for Parkinson′s Research (MJFF). S.v.V. was supported by postdoctoral fellowships from the FWO (1253721N) and KU Leuven (PDMt1/24/010).

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This study was approved by the ethics committee of the University of Leipzig (402/16-ek). Written informed consent for molecular genetic testing and data publication was obtained from the individual and/or their legal representatives by the referring physicians.

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All datasets generated or analyzed in this study can be found through the Zenodo repository at DOI: https://doi.org/10.5281/zenodo.14719448 (Figures) and DOI: https://doi.org/10.5281/zenodo.14717838 (Extended Data Figures). All experimental protocols are shared via protocols.io at DOI: dx.doi.org/10.17504/protocols.io.4r3l29p3xv1y/v1. These datasets and protocols will be made publicly available as of the date of publication. All original code has been deposited at the Eroglu lab GitHub site (https://github.com/Eroglu-Lab/). Respective DOIs are listed in the Key Resources Table. For the purpose of open access, the author has applied a CC BY 4.0 public copyright license to all Author Accepted Manuscripts arising from this submission.