In this illustration, BDNF is represented as a train travelling along the signalling pathway identified in the study. This pathway leads to an increase in NMDA receptors at synapses, strengthening communication between neurons. Each star represents neuronal activity: the more stars, the higher the neuronal activity. When this signalling pathway is blocked, the effect of BDNF no longer occurs, revealing a molecular mechanism that could help prevent the brain hyperexcitability associated with epilepsy. Understanding this process may contribute to the development of future therapeutic strategies aimed at limiting disease progression.
A research team from the University of Coimbra's Centre for Neuroscience and Cell Biology (CNC-UC) and the Center for Innovation in Biomedicine and Biotechnology (CiBB), led by Carlos B. Duarte, have uncovered molecular mechanisms that shed light how a protein naturally present in the brain contributes to the development of epilepsy. The discovery could help guide future strategies aimed at slowing the progression of the disease.
The findings, published in the journal Brain, show how elevated levels of the protein known as brain-derived neurotrophic factor (BDNF) promote the development of epilepsy. BDNF plays a crucial role in the functioning of the nervous system, regulating communication between neurons and supporting neuronal plasticity, which is essential for learning and memory formation. Although BDNF's involvement in epilepsy has long been recognized, the cellular mechanisms underlying its effects have remained largely unclear.
Epilepsy affects around 50 million people worldwide and is characterized by recurrent seizures caused by excessive and synchronized electrical activity in the brain. Using an animal model of the disease, the CNC-UC research team demonstrated that BDNF increases the number of glutamate receptors at synapses, the brain regions where neurons communicate with one another. This increase makes nerve cells more responsive to signals from neighboring neurons, strengthening neuronal communication. As a result, it may contribute to the brain hyperactivity that is characteristic of epilepsy.
"This work provides new insights into how BDNF, a protein naturally produced by the brain, enhances communication between neurons and identifies a mechanism that contributes to brain hyperactivity, ultimately triggering epileptic seizures," explains Carlos B. Duarte, Principal Investigator at CNC-UC and Professor in the Department of Life Sciences at the Faculty of Sciences and Technology of the University of Coimbra.
Research Team: Rui O.Costa, Francesca Napoli, Carlos B.Duarte, Miranda Mele e Philemon Mshelia
The study also identified the cellular signalling pathway responsible for this process. By activating its receptor on the surface of neurons, BDNF triggers a cascade of molecular events that ultimately increases the expression of NMDA receptors on the neuronal plasma membrane. When this signalling pathway is blocked, the changes induced by BDNF no longer occur, confirming the key role of this mechanism in neuronal hyperexcitability.
The findings also open the possibility of investigating this mechanism in other neurological disorders in which communication between neurons is disrupted, affecting fundamental brain functions such as learning and memory.
The scientific paper GluN2A-NMDA receptors mediate the effect of BDNF on network hyperexcitability in hippocampal neurons is available here.
