Neurons Can Stabilize Brain Communication Using Physical Signals Instead of Electricity

Every movement you make, every thought you form, and every memory you store depends on neurons talking to each other with remarkable precision. When this communication breaks down, even briefly, the brain must act fast to restore balance. A new study from researchers at the USC Dornsife College of Letters, Arts and Sciences reveals something surprising about how this recovery happens. Contrary to long-held assumptions, neurons don’t always rely on electrical activity to stabilize communication. Instead, they can use physical, structural signals to keep neural circuits functioning smoothly.

The research, published in Proceedings of the National Academy of Sciences (PNAS) in 2025, introduces a previously unrecognized mechanism that allows neurons to rapidly rebalance their signaling when part of a synapse suddenly stops working. This discovery reshapes how scientists understand brain stability and opens new doors for studying neurological disorders.

Why Neuronal Balance Matters

Neurons communicate at junctions called synapses, where one neuron sends chemical signals to another. For the brain to work properly, this communication must stay within a carefully controlled range. Too much signaling or too little can cause serious problems. This balance, known as synaptic homeostasis, is essential for muscle control, learning, memory formation, and overall brain health.

When homeostasis fails, it has been linked to neurological conditions such as epilepsy, autism, and other disorders involving abnormal neural activity. For decades, scientists believed that electrical signals—specifically the movement of charged ions across neuron membranes—were required for neurons to sense problems and correct them. This new research challenges that idea in a big way.

The Central Question Behind the Study

The research team, led by Dion Dickman, professor of biological sciences at USC Dornsife, wanted to answer a very specific question:
How does the receiving side of a synapse detect that something has gone wrong and quickly tell the sending neuron to adjust its output?

More precisely, they focused on what happens when postsnyaptic receptors, which normally receive neurotransmitters, suddenly stop working. How does the neuron notice the failure, and how does it signal back to restore balance?

Using Fruit Flies to Understand the Brain

To investigate this, the researchers used fruit flies (Drosophila melanogaster), a well-established model organism in neuroscience. Despite their simplicity, fruit flies share many fundamental neural mechanisms with humans, making them ideal for studying basic brain processes.

The team chemically blocked glutamate receptors on the receiving side of the synapse. These receptors normally respond to glutamate, one of the brain’s primary excitatory neurotransmitters. Blocking them effectively simulated a sudden loss of synaptic function.

Using a combination of electrical recordings and high-resolution microscopy, the scientists closely observed how the synapse responded to this disruption. They also used CRISPR gene-editing technology to remove specific proteins one by one, allowing them to pinpoint which molecules were essential for the rapid recovery process.

A Surprising Discovery: Structure Over Electricity

What they found overturned a core assumption in neuroscience. The trigger for rapid synaptic compensation was not a drop in electrical activity. Instead, it was a physical reorganization of receptors within the synapse.

When the glutamate receptors were blocked, they didn’t just become inactive. They rearranged themselves structurally inside the postsynaptic region. This physical change acted as a signal—essentially a structural alarm—that something was wrong.

That structural rearrangement then initiated a retrograde signaling process, meaning the signal traveled backward across the synapse. The receiving neuron instructed the sending neuron to release more neurotransmitters, compensating for the loss of receptor activity and restoring stable communication.

The Critical Role of the DLG Protein

One protein turned out to be absolutely essential for this mechanism: DLG, a scaffold protein that helps organize synaptic components. Scaffold proteins act like molecular frameworks, keeping receptors and signaling molecules in the right places.

When the researchers removed DLG using CRISPR, the rapid compensatory response failed entirely. Without DLG, the receptors could not reorganize properly, and the synapse lost its ability to stabilize communication quickly. This confirmed that structural organization, not electrical signaling, was driving the process.

Proof That Electricity Isn’t Required

To make the findings even more convincing, the team went a step further. They completely silenced all electrical synaptic activity and observed what happened. Remarkably, the fast stabilization mechanism still worked.

This showed definitively that the process is nonionic, meaning it does not depend on the movement of charged particles. The brain, it turns out, has a backup communication system that relies on physical changes at the synapse rather than electrical signals.

What Is Nonionic Signaling?

Nonionic signaling refers to communication mechanisms that do not rely on ions flowing across membranes. In this case, the signal comes from structural rearrangements of proteins and receptors. These physical changes can be detected by other molecular components, triggering downstream responses without altering electrical activity.

This idea expands the traditional view of how neurons communicate. The brain is not just an electrical network; it is also a mechanical and structural system, capable of sensing and responding to physical changes at a microscopic level.

Why This Discovery Matters

This research has major implications for neuroscience. First, it redefines synaptic homeostasis, showing that neurons have faster and more versatile ways to stabilize communication than previously believed.

Second, it offers new insight into neurological disorders. If conditions like epilepsy or autism involve failures in synaptic stability, then structural signaling pathways may be just as important as electrical ones. Understanding these pathways could eventually guide new therapeutic strategies aimed at strengthening neural resilience.

Finally, the study highlights how adaptable the brain really is. Even when traditional electrical communication fails, neurons can still find ways to maintain balance and keep circuits functioning.

Extra Insight: Homeostatic Plasticity in the Brain

Homeostatic plasticity is the brain’s way of maintaining stability while still allowing flexibility. Unlike learning-related plasticity, which strengthens or weakens specific synapses, homeostatic plasticity adjusts overall activity levels to prevent runaway excitation or complete silence.

This newly discovered structural mechanism fits perfectly into that framework. It acts as a rapid, local correction system, ensuring that short-term disruptions don’t spiral into long-term dysfunction.

Looking Ahead

The researchers believe this is just the beginning. Similar structural signaling mechanisms may exist in other parts of the brain and in other species, including humans. Future studies will explore whether these pathways can be targeted to improve brain health or slow the progression of neurological diseases.

What’s clear already is that neurons are far more resourceful than once thought. They don’t just rely on electricity. They also listen to shape, structure, and physical organization to keep the brain running smoothly.

Research Paper Reference:
https://www.pnas.org/doi/10.1073/pnas.2502997122