• Discovery of a precise molecular process: Researchers identified how two proteins, BDNF and MMP-9, work together to strengthen brain connections, a process essential for learning.
• Real-time visualization: Using advanced microscopy, the team showed that MMP-9 activates BDNF exactly where a connection is stimulated, ensuring only the correct synapses are strengthened.
• Implications for brain health: This breakthrough helps explain how the brain adapts with precision and may open new paths for treating disorders linked to disrupted synaptic plasticity, including schizophrenia, depression, addiction, and epilepsy.

Scientists from the Nencki Institute and the Max Planck Florida Institute for Neuroscience have revealed a key mechanism in how our brains change when we learn new information or form memories. A new study published in Science Advances reveals a molecular mechanism that allows brain cells to precisely strengthen specific connections – a process essential for learning, memory, and overall brain health.

Understanding How Brain Connections Adapt

The human brain contains billions of neurons that communicate through connections called synapses. These connections aren't fixed. They can become stronger or weaker depending on our experiences, a phenomenon scientists call "synaptic plasticity." This term was introduced to science by a Polish researcher from the Nencki Institute — Jerzy Konorski in 1948. This ability to change is fundamental to how we learn, remember, and adapt to new situations.

Because problems with synaptic plasticity are linked to serious conditions like schizophrenia, depression, addiction, and epilepsy, neuroscientists are focused on understanding how brain cells work together at the molecular level to reshape their connections. Until recently, most research has focused on what happens inside brain cells, but much less is known about the critical processes that occur in the space between cells.

This week, a research team led by Prof. Leszek Kaczmarek and Dr Piotr Michaluk of the Nencki Institute, together with Prof. Ryohei Yasuda of the Max Planck Florida Institute for Neuroscience, described how two proteins interact in the space between neurons to strengthen specific connections.

"We knew that certain proteins were important for synaptic plasticity, but we didn't understand how they worked together in real-time at individual brain connections," said Dr Diana Legutko, the leading scientist of the study. "This gap in knowledge has been a fundamental barrier to understanding how healthy brains actually function and what goes wrong in neurological disorders."

A Molecular Partnership Revealed

Using advanced microscopy techniques that can observe individual brain cell connections in real-time, the research team discovered that two crucial proteins – BDNF (brain-derived neurotrophic factor) and MMP-9 (matrix metalloproteinase-9) – work together in a precisely coordinated dance to strengthen synapses.

They work as follows: When a brain connection is activated, both proteins are rapidly released by a neuron. BDNF acts like a "growth signal" that tells the connection to get stronger, but it is released in an inactive form that can't do its job. That's where MMP-9 comes in – this protein acts like a molecular scissors, trimming BDNF into its active form right at the specific connection that needs to be strengthened.

"What's remarkable is the precision of this system," explained Dr Piotr Michaluk, co-author of the study. "The MMP-9 protein only becomes active exactly where and when it's needed – at the stimulated connection – ensuring that only the right synapses get strengthened."

The Bigger Picture: From Lab to Life

This finding helps address a long-standing puzzle about how brain connections change with such precision. The research provides the missing link in our understanding of how learning and memory work at the molecular level, showing that synaptic plasticity isn't just about having the right proteins present, but about having them work together with perfect timing and location.

"This discovery gives us a much clearer picture of how healthy brains maintain the ability to learn and adapt throughout life," said Prof. Leszek Kaczmarek. "The hope is that we can use this information to help understand what goes wrong in brain disorders and effectively intervene.”

One of the challenges in developing therapeutics that target synaptic plasticity is ensuring that only the specific connections that should be strengthened are affected. The precise nature of the MMP-9/BDNF interaction offers potential new targets for medications that could restore healthy brain plasticity in various disorders.

The team plans to investigate whether disruptions in the timing of MMP-9/BDNF interaction contribute to plasticity problems in models of specific disorders. “Whether disruptions in this mechanism contribute to problems of brain plasticity in the context of disease is an important next step,” said Prof. Ryohei Yasuda. "One of the big questions now is whether this finding can lead to more targeted and precise treatments."

https://www.science.org/doi/10.1126/sciadv.adx2369

This research was funded by the National Science Centre MAESTRO grant (Poland), the National Agency for Academic Exchange (Poland), the National Institutes of Health and the Max Planck Society. This content is solely the authors’ responsibility and does not necessarily represent the official views of the funders.