A single neural mechanism might finally explain schizophrenia, depression, and PTSD

New evidence suggests that a single biophysical mechanism — the gradual collapse of neural excitability margins — may underlie schizophrenia, depression, and PTSD alike.

For decades, psychiatry has struggled to connect the dots between disorders that seem different but share overlapping symptoms — from hallucinations to intrusive memories and emotional numbness.

Despite thousands of studies and competing hypotheses, the field still faces the same paradox: Why do so many psychiatric conditions — schizophrenia, depression, PTSD — appear to emerge from stress, yet express themselves so differently?

What if, in reality, all known risk factors — from chronic stress and sleep deprivation to genetics, infections, or even microplastics — converge on one simple mechanism?

A gradual narrowing of the margin between a neuron’s resting potential and its firing threshold.

The collapse of emotional safety margins

Through a multi-layered analysis of cellular and molecular pathways, I found that stress alone can reduce this excitability margin by up to 11.3 millivolts — primarily through four independent mechanisms involving KCC2, NKCC1, ATP, and GIRK channel regulation.

Each pathway acts like a small lever, shifting the brain toward higher excitability and lowering the amount of energy required to activate a memory or emotion.

Further examination of dozens of established risk factors led to the same conclusion.

Infections and high-sugar diets narrow the margin via IL-6–mediated inflammation, while caffeine disrupts inhibitory balance by blocking GIRK channels.

Genetic or environmental factors, in turn, often prolong the time required to integrate incoming signals or lower the rheobase current — the amount of charge needed to make a neuron fire.

In each case, the effect is the same: the energy gap between rest and activation shrinks.

Every variant, no matter the pathway, ultimately makes it easier for memory-related neurons to activate.

However, repeated activation of the same emotional-memory cells revealed something even more striking.

Each time these neurons were reactivated — for instance, during stress-related replay or intrusive recall — their excitability margin itself shrank further, by as much as 3 millivolts in roughly 5% of cells.

From emotional memory to uncontrolled replay

In the ventral CA1 subfield of the hippocampus — the region that stores emotionally charged memories — this means that the original 20-millivolt gap between rest and firing can collapse to just 2–3 mV.

At that point, even the brain’s natural oscillations — such as theta (5–8 Hz), gamma (30–45 Hz), or dendritic plateau potentials reaching amplitudes of up to 6 mV — can trigger uncontrolled activation of thought and memory patterns in that vulnerable 5% of cells.

And here comes the most revealing part.

Which memories or emotions become unstable depends entirely on which neurons were activated most often.

If the cells repeatedly engaged were those encoding fear, they are the ones most likely to undergo a critical narrowing of their excitability margin — making them prone to spontaneous reactivation by ordinary network oscillations.

If the overused cells encoded traumatic experiences, those circuits become hypersensitive, leading to uncontrolled flashbacks or vivid intrusive memories.

And if the chronically active networks encoded sadness or hopelessness, the same mechanism would cause recurring, involuntary activation of depressive thoughts.

In essence, the brain begins to replay whatever it has practiced the most — not by choice, but by physics.

The biochemical echo of fear

But that’s not all.

Each spontaneous activation also sets off a powerful neurochemical cascade.

When a “fear cell” in ventral CA1 reactivates, it sends excitatory input to the mesolimbic dopamine pathway — triggering dopamine release from the ventral tegmental area (VTA) — while simultaneously stimulating the hypothalamic–pituitary–adrenal (HPA) axis, leading to elevated cortisol production.

In other words, every uncontrolled activation not only replays an emotion, but chemically reinforces the stress state that caused it in the first place.

The self-reinforcing vicious cycle

Each uncontrolled activation doesn’t just replay the emotion — it creates new stress.

This, in turn, keeps the excitability margin critically low, locking the system into a self-reinforcing loop.

Every burst of activity releases reactive oxygen species (ROS); and as the brain’s supply of protective glutathione runs out, oxidative stress begins to damage the surrounding perineuronal networks.

As these networks break down, PV-interneurons — the cells responsible for stabilizing gamma oscillations — lose their synchrony and inhibitory control.

The result is even weaker network inhibition, which allows still more spontaneous activations to occur.

Once the excitability margin falls below the critical threshold, the system effectively traps itself in a vicious cycle: stress begets activation, activation begets damage, and damage begets still more stress.

Uncontrolled activation of fear circuits reproduces the core features of schizophrenia

When this model was compared against the full spectrum of neurobiological findings in schizophrenia, the match was striking.

Every major anomaly observed in patients aligns with what would be expected from a critically reduced excitability margin.

The hyperactivity of ventral CA1, repeatedly shown in fMRI and electrophysiological studies, fits perfectly: this is the very region where, according to the model, uncontrolled reactivations of memory cells occur.

The elevated dopamine release in the mesolimbic pathway — long considered the biochemical hallmark of schizophrenia — emerges naturally from repeated, spontaneous activations of fear cells.

The chronic depletion of glutathione, frequently reported in patients, also follows directly: continuous bursts of uncontrolled activity produce excessive ROS, gradually exhausting the brain’s antioxidant reserves.

Likewise, the observed disruption of gamma oscillations reflects the secondary damage to PV-interneurons and their surrounding perineuronal nets, which are among the first structures to degrade under oxidative stress.

Intriguingly, several recent studies have also reported pathological activations driven directly by gamma oscillations themselves — without any external stimulus.

These spontaneous gamma bursts, observed in both animal models and human recordings, have puzzled researchers for years.

Within the excitability-margin framework, however, they make perfect sense: once the safety buffer collapses, even ordinary gamma cycles can inject enough voltage to trigger runaway firing in the most unstable networks.

Together, these findings suggest that schizophrenia may not stem from a single receptor malfunction or neurotransmitter imbalance, but from a network-level energy collapse — a progressive loss of the brain’s safety margin.

When one disorder becomes another: how collapsing networks can turn depression into schizophrenia

A similar logic applies to other disorders.

When the unstable neurons encode traumatic experiences, their reactivation leads to the neurochemical cascades characteristic of PTSD.

When the same process affects networks encoding sadness or hopelessness, it manifests as major depression.

Different symptoms — same underlying mechanism: the collapse of the excitability margin.

But the story doesn’t end there.

Neurons that have entered this critical low-margin state appear to pull neighboring clusters into instability.

If a person experiencing uncontrolled activations in “sadness” circuits (depression) begins to recruit adjacent “fear” clusters, the network can gradually shift toward a psychotic configuration.

In other words, depression may evolve into schizophrenia when emotional networks merge through overlapping activations.

This also explains why the course of psychiatric illness differs so widely between individuals:

the outcome depends not on a single molecular defect, but on which emotional circuits dominate once the excitability margin collapses.

For some, the reactivations center on sadness.

For others, on fear or trauma.

Same physics — different experience.

References & further reading

This article is based on “Ventral CA1 excitability-margin collapse as a unifying trigger of emotional replay in schizophrenia, depression, and PTSD” (Rosa, 2025), which proposes a unified framework linking stress, excitability collapse, and emotional-memory replay in psychiatric disorders.

📄 Full preprint: https://doi.org/10.31219/osf.io/e4cwb

🧠 Independent PREreview: https://prereview.org/reviews/17196364

🎥 9-minute explainer video: https://www.youtube.com/watch?v=DWbEN-F5MLY

About the author

Patryk Rosa is the author of the Excitability-Margin Model (EMM) — a unified neuroenergetic framework explaining how stress and cellular excitability shape emotional replay, memory, and psychiatric symptom formation.

He combines theoretical modeling with translational neuroscience to bridge molecular findings with network-level dynamics.