Summary: New preclinical work shows that boosting the astrocyte-secreted protein pleiotrophin (Ptn) in adult Down syndrome model mice reverses deficits in neuronal branching and restores hippocampal electrical activity. Researchers used adeno-associated viruses (AAVs) to deliver the Ptn gene to astrocytes across the brain; treated mice showed recovery in the visual cortex and hippocampus to levels similar to control animals. While promising, these results are limited to mouse models and require further safety and translational studies before any human applications.
Astrocyte protein pleiotrophin (Ptn) can “rewire” neural circuits and restore function in Down syndrome mice
Summary: New preclinical work shows that boosting the astrocyte-secreted protein pleiotrophin (Ptn) in adult Down syndrome model mice reverses deficits in neuronal branching and restores hippocampal electrical activity. Researchers used adeno-associated viruses (AAVs) to deliver the Ptn gene to astrocytes across the brain; treated mice showed recovery in the visual cortex and hippocampus to levels similar to control animals. While promising, these results are limited to mouse models and require further safety and translational studies before any human applications.
01:16 AM, 11/12/2025Science
Astrocyte protein pleiotrophin (Ptn) can “rewire” neural circuits and restore function in Down syndrome mice
New preclinical research published in Cell Reports shows that increasing levels of a single astrocyte-derived protein, pleiotrophin (Ptn), can reverse structural and functional deficits in the brains of adult mice modeling Down syndrome. Delivering the Ptn gene to astrocytes across the brain restored neuronal branching in the visual cortex and hippocampus and normalized hippocampal electrical activity.
Background
Down syndrome results from trisomy of chromosome 21, which duplicates genes encoded on that chromosome and leads to changes across multiple organ systems, including neurodevelopmental alterations. Neuronal structure and connectivity are altered in people with Down syndrome and in mouse models of the condition. Astrocytes—star-shaped glial cells with many thin processes—both shape synapses and secrete proteins essential for proper neuronal wiring.
Identifying a candidate: pleiotrophin (Ptn)
Proteomic analyses of astrocytes from a Down syndrome mouse model revealed several proteins whose levels are altered during development. The research team focused on proteins reduced in Down syndrome astrocytes; one top candidate was pleiotrophin (Ptn), a secreted molecule known to guide axons during development. Because axon guidance and dendritic branching are related aspects of circuit wiring, the authors hypothesized that reduced Ptn could contribute to the decreased neuronal branching seen in Down syndrome models.
Key experiments and findings
First, the researchers confirmed that mice genetically engineered to lack Ptn had neurons with reduced branching, mirroring the cellular phenotype of the Down syndrome model mice. This finding supported a role for Ptn in promoting normal neuronal arborization.
To test whether restoring Ptn in astrocytes could repair circuits in adult animals, the team packaged the Ptn gene into adeno-associated viruses (AAVs) with their replication genes removed—an established tool for targeted gene delivery. They used these AAVs to increase Ptn production specifically in astrocytes across the brains of adult Down syndrome model mice.
After treatment, both the visual cortex (important for processing sight) and the hippocampus (critical for memory) showed recovery of neuronal branching density to levels similar to control mice. Electrophysiological recordings demonstrated that hippocampal electrical activity—an indicator of circuit function—was restored to values indistinguishable from unaffected mice.
Implications and caveats
Taken together, these results indicate that boosting a single astrocyte-derived protein can reverse structural and functional deficits in adult mammalian brains in this Down syndrome model. The findings highlight the broader potential of manipulating astrocyte-secreted proteins to modify adult neural circuits in other neurodevelopmental conditions (for example, Fragile X syndrome or Rett syndrome) and possibly in neurodegenerative diseases such as Parkinson’s disease.
However, several important caveats remain. These are preclinical results in mouse models, and mouse neurobiology does not fully recapitulate human brain complexity. AAV-based gene delivery raises questions about long-term safety, immune responses, dosage, and specificity. Off-target effects and differences among Down syndrome patients must be carefully examined. Extensive additional research—across multiple models, ages, and safety studies—would be needed before considering clinical translation.
Publication and authorship
This article summarizes research published in Cell Reports and was written by Ashley Brandebura, University of Virginia. Funding disclosures in the original work include NIH NINDS and NIA support.
Bottom line: In mouse models of Down syndrome, increasing astrocyte production of pleiotrophin can reverse neuronal branching deficits and restore hippocampal activity, revealing a promising—but early and preclinical—approach to rewiring adult neural circuits.