A team of neuroscientists from the Salk Institute has shown that targeting astrocytes – supportive brain cells that manage the chemical environment of neurons and secrete substances important for synapses – can change the functioning of brain circuits even in adulthood. The focus was on the protein pleiotrophin, a natural growth factor that, in healthy nervous system development, participates in the maturation of axons and dendrites and promotes the establishment of synaptic connections. In a Down syndrome model, the levels of this protein decrease, and the team investigated whether restoring them could reverse some of the neurological consequences.

Why astrocytes have come into the spotlight

Astrocytes were long considered the "support staff" for neurons, but in recent years they have been shown to be active regulatory players that thermally, metabolically, and signaling-wise modulate the function of neural networks and influence plasticity, i.e., the brain's ability to change and adapt synaptic connections. The laboratory of the study's lead researcher at the Salk Institute, neuroscientist Nicole J. Allen, systematically studies how proteins secreted by astrocytes at different life stages – from early development, through adulthood, to aging – modulate the stability and renewability of synapses. Some of these molecules promote the formation of new synapses in early development, while another set stabilizes synapses in adulthood, thereby limiting plasticity, which can be a double-edged sword in brain diseases.

The key target: pleiotrophin and the "reset" of synaptic communication

In their latest paper published last month in the journal Cell Reports, the team led by Ashley N. Brandebura and Nicole J. Allen identified that in the brains of mice modeling Down syndrome (the Ts65Dn line), there is a markedly reduced level of pleiotrophin secreted specifically by astrocytes. When the scientists specifically increased the levels of this protein in astrocytes, they observed corrections in dendrite structure, an increase in synapse density, and improvements in functional synaptic signaling, especially in the hippocampus – the center for learning and memory. Such targeted overexpression of pleiotrophin in astrocytes acted as a kind of "reset" for synaptic communication in adulthood.

How the therapeutic signal was delivered to the cells

To reach the astrocytes, the researchers used virus-derived vectors – technological "envelopes" from which harmful components were removed and the genetic code for pleiotrophin was inserted. This approach allows targeted brain cells to temporarily and controllably produce the desired protein, without the systemic administration of drugs that could have broader effects. In this study, the vectors were directed at astrocytes, which enabled the precise delivery of a molecule that indirectly "rewires" neural networks. Importantly, the changes were observed in adult mice – that is, after the brain had already formed – suggesting that therapies targeting astrocytes could have a window of action even beyond the prenatal period.

What this means for Down syndrome

Down syndrome (trisomy 21) is the most common chromosomal disorder associated with intellectual disabilities. In the United States, it is estimated that approximately 5,700 babies are born with this condition each year, corresponding to a frequency of about one in 640 live births; the life expectancy of people with Down syndrome has significantly increased in recent decades thanks to advances in medicine and care. However, challenges in speech development, memory, attention, and behavior, as well as a higher incidence of heart defects, thyroid problems, and hearing and vision issues, remain pronounced and require comprehensive, multidisciplinary support approaches.

Understanding the biological basis of these difficulties is crucial for developing targeted interventions. The Ts65Dn mouse strain has been the standard experimental model for Down syndrome for decades: it exhibits described impairments in neurogenesis, changes in the hippocampus, and limited plasticity, which are linked to learning and memory deficits. The new paper specifically links the decrease in pleiotrophin secreted by astrocytes to the dendritic and synaptic changes typical of this model, and the restoration of pleiotrophin led to structural and functional improvements.

From the Salk lab to the University of Virginia

Ashley N. Brandebura began the research as a postdoctoral fellow in Nicole J. Allen's laboratory at the Salk Institute, one of the world's leading centers for molecular neurobiology. After completing her postdoc in 2025, she opened her own laboratory at the University of Virginia (UVA) School of Medicine, where she continues to study how astrocytes, in interaction with other glial cells and the blood-brain barrier, shape synaptic balance in neurodevelopmental and neurodegenerative conditions. Her research focus includes perineuronal nets and plasticity, interferon signaling in Down syndrome, and the breakdown of communication between astrocytes and microglia.

In the context of the latest paper, Brandebura emphasizes that the results serve as a proof of concept: targeting astrocytes, cells specialized in secreting molecules that remodel synapses, can enable the "rewiring" of brain circuits even in adulthood. Although application in humans is still a long way off, the findings open up the possibility that in the future, therapeutic proteins, like pleiotrophin, could be delivered via gene therapy or even protein infusions, with the aim of improving the quality of life for people with Down syndrome.

How the new discoveries fit into the broader scientific picture

The work deepens the growing body of research that places astrocytes at the very center of brain health and disease. It has been shown, for example, that astrocytes adopt properties during aging that negatively affect neurons, that in adulthood they secrete proteins that stabilize synapses and reduce plasticity, and that manipulating these target molecules can change the outcome of recovery after injury. The observation that restoring pleiotrophin in astrocytes can enhance synaptic dynamics and enable better learning, at least in an animal model, fits quite naturally into this picture.

Support and research infrastructure

The research was supported by a combination of philanthropic and public funds, including programs that encourage the early careers of researchers and the creation of networks dedicated to neurodegenerative diseases. Such investments enable long-term, high-risk, and innovative projects – such as the systematic mapping of astrocytic proteins and examining how changes in their secretion during development affect the final "wired" outcome of the brain. In the past, such initiatives have enabled the Salk lab to identify hundreds of astrocytic proteins whose levels are altered in the Down syndrome model, among which pleiotrophin stood out as a particularly interesting target.

Methodological framework: from proteome to function

The starting point was to discover which specific proteins were different in the brains of the Down syndrome model. The authors combined quantitative analyses of secreted astrocyte proteins with neuron morphometry and electrophysiological measurements of synaptic function. A comparison of the Ts65Dn line and mice without pleiotrophin showed overlaps – which was a strong signal that the lack of pleiotrophin is important in the development of dendritic and synaptic anomalies. When the researchers then selectively increased pleiotrophin production in astrocytes, there was an increase in the number and stability of synapses and functional improvements in signal transmission, which they confirmed with measurements in the hippocampus.

What "targeting astrocytes" means and why it is important

Traditional therapeutic attempts in neuroscience have often been directed at neurons themselves or at mutated genes. But the brain is an ecosystem, and astrocytes perform a range of tasks within it: they supply neurons with energy, maintain ion balance, recycle neurotransmitters, shape synaptic contacts, and participate in immune responses. Therefore, interventions that "strengthen" their beneficial functions or correct disturbances in protein secretion can have a broader, systemic effect on networks. Additionally, astrocytes are more numerous than neurons and are spatially distributed to "oversee" many synapses, making them natural distributors of signaling molecules in the brain.

Limitations and caution in interpretation

Although the results are robust, the authors emphasize that pleiotrophin is not the only factor contributing to the disruption of brain circuits in Down syndrome. It is a complex condition in which numerous genes, developmental time windows, and environmental influences interact, so it is unlikely that a single molecule will be a universal "switch." However, the fact that targeting astrocytes in adulthood led to improvements in the disease model strongly motivates further research into ways to "reprogram" dysfunctional astrocytes to deliver synaptogenic agents.

Potential applications beyond Down syndrome

The concept that astrocytes can deliver molecules that activate plasticity also opens doors to other conditions. Scientists are considering neurodevelopmental disorders like fragile X syndrome, as well as neurodegenerative diseases, such as Alzheimer's disease, where synaptic dysfunction is one of the earliest and most reliable biomarkers of cognitive decline. If it were proven that precise dosing of molecules like pleiotrophin in the right cells and at the right time could stimulate synapse renewal, then a whole new class of therapies that modulate plasticity instead of targeting individual neurotransmitters or receptors could theoretically be developed.

What's next: the path from mouse to human

Translating findings from mouse to human involves a series of steps: confirming that similar mechanisms are at play in the human brain, developing vectors and dosing regimens that are safe for humans, precisely determining the time windows and duration of application, and establishing clear biological and clinical endpoints. Additionally, it is necessary to assess how long the effects of a single cycle of enhanced pleiotrophin expression in astrocytes last, as well as whether there is a risk of "excessive" stimulation of growth and synaptic remodeling that could disrupt network stability or cause undesirable outcomes. Such assessments require a parallel foundation in basic science and carefully designed early clinical studies.

Knowledge infrastructure and open questions

At the level of basic biology, it remains to be clarified how exactly pleiotrophin expression is regulated in astrocytes during development, which signaling axes most influence its secretion, and through which pathways it acts on neurons in specific brain regions. In the Ts65Dn model, multiple changes in the hippocampus have already been documented, including reduced neurogenesis and altered patterns of synaptic plasticity; the new observations link these phenotypes to a pleiotrophin deficit, but imaging at the level of individual synapses and networks is needed to deconstruct all contributing factors. On the practical side, it is of great importance to standardize methods for targeting astrocytes and quantifying changes, and to develop biomarkers that could in the future serve to monitor the effect of therapies.

Where readers can find more information

Details about the scientific paper are available in the open-access abstract of the publication in the journal Cell Reports, while information about the research programs and goals can be found on the websites of the Salk Institute and the University of Virginia School of Medicine. Interested readers can also look at resources intended for families and professionals working with individuals with Down syndrome, where current guidelines for healthcare and support in education and social inclusion are summarized.