New Publications How neurons regulate their architecture: Key mechanism balancing neuronal structural stability and plasticity uncovered

The group led by Prof. Dr. Daniela Mauceri has discovered a novel mechanism by which neurons maintain the balance between structural plasticity and stability—a crucial equilibrium for proper brain function and memory formation. The researchers demonstrated that the level of the secreted molecule VEGFD (Vascular Endothelial Growth Factor D) is key in this process. The findings were published in the journal Cellular and Molecular Life Sciences. 

One of the key features of neuronal architecture is their dendritic tree through which connections with other nerve cells are ensured and forming the network essential for brain function. While the structure of dendrites from mature neurons is predominantly stable, a certain quota of structural plasticity is needed to enable adaptive processes like memory formation. Thus, from a structural perspective, neurons face the challenge of balancing these competing needs, and until now, the molecular mechanisms governing this balance were not understood. Gaining a deeper understanding of these processes is essential, as disruptions in dendritic architecture—whether due to atrophy or maladaptive plasticity—can result in abnormal connectivity, contributing to various neurological disorders.

The study discovered that neurons precisely regulate VEGFD levels to balance dendritic structural plasticity and stabilization. Using mouse cell cultures and in vivo mouse models, the researchers demonstrated that, in response to remodeling-inducing signals, such as increased synaptic activity or fear memory formation, neurons downregulate VEGFD to allow structural plasticity. On the other hand, a series of experiments carried out by Dr. Bahar Aksan, first author of the study, demonstrated that when VEGFD levels were maintained, structural plasticity was inhibited. Mechanistically, the neurobiologists observed that VEGFD modulates the cytoskeleton—the cell's structural scaffold—, reduces dendritic elongation and destabilizes newly formed dendrites. Moreover, the team described the VEGFD signaling cascade linking the secreted molecule to cytoskeleton elements. These findings show that VEGFD acts as a molecular brake on morphological changes. 

Interestingly, the study found that spatial memory formation was aberrantly enhanced in mice in which fear memory-induced dendritic changes were inhibited through blocking of VEGFD downregulation. There are various mechanisms that have been identified as memory suppressors, supporting the hypothesis that there may be a biological need to limit memory formation. VEGFD downregulation and activity-dependent dendritic remodeling may thus be another such control mechanism in memory formation. 

These findings open new avenues for therapeutic development. By targeting the VEGFD signaling pathway or its expression mechanisms, it may be possible to develop novel treatments for neurological diseases characterized by dendritic atrophy or maladaptive plasticity.

The research work was funded by the German Research Foundation, the Alzheimer Forschung Initiative, the Chica and Heinz Schaller Foundation and the Joachim Herz Foundation.