Seizures suppress follistatin, disrupting neurogenesis in Alzheimer's disease

In the hippocampus—the brain region essential for forming new memories—something goes wrong when seizures strike. Neurons that should be born and integrated into existing circuits fail to develop properly. This disruption of adult neurogenesis has long been observed in Alzheimer's disease and other seizure-prone neurological conditions, but the molecular pathway responsible remained opaque. A new study published in Nature Communications identifies follistatin, a protein that regulates growth factors in the brain, as the linchpin connecting seizure activity to the breakdown of neurogenesis.

Researchers working with mouse models of Alzheimer's neuropathology discovered that follistatin expression plummets in the dentate gyrus—a subregion of the hippocampus where new neurons are born throughout life—when animals experience spontaneous seizures similar to those that occur in people with Alzheimer's. The finding emerged from a systematic investigation of how seizure-induced changes in gene expression cascade through the brain's neurogenic machinery. When the team treated these Alzheimer's mice with an antiseizure medication, follistatin levels rebounded. Conversely, when they administered a seizure-inducing agent to healthy mice, follistatin expression dropped sharply. The pattern was consistent and reproducible: seizures suppress follistatin; suppressing seizures restores it.

The researchers then traced the molecular chain of command. They identified c-Fos, a gene that normally activates follistatin production, as the critical intermediary. But seizures interfere with this activation through a transcription factor called ∆FosB, which is induced by seizure activity and actively suppresses c-Fos expression. This creates a bottleneck: seizures trigger ∆FosB, ∆FosB silences c-Fos, c-Fos cannot activate follistatin, and follistatin levels collapse. The mechanism is activity-dependent—meaning the brain's electrical state directly controls whether this regulatory pathway functions or fails.

To confirm follistatin's causal role, the team performed two complementary experiments. In one, they genetically ablated the Fst gene in healthy mice and observed that neurogenesis became dysregulated—the normal rhythm of neural stem cell proliferation and differentiation went awry. In the other, they administered follistatin directly to Alzheimer's mice and watched as neurogenesis dynamics normalized, restoring the proper sequence of events that allows new neurons to mature and integrate into circuits. Neither manipulation altered the seizures themselves; the effect was specific to the neurogenic process downstream.

The implications are substantial. Seizures are common in Alzheimer's disease, occurring in roughly one-third of patients, and they are associated with accelerated cognitive decline. Current treatments focus on stopping seizures through antiseizure drugs, but the mechanism by which seizures damage the brain's capacity to generate new neurons has remained unclear. This work suggests that the damage flows through follistatin suppression, and that restoring follistatin—either by controlling seizures or by direct protein replacement—might preserve or restore neurogenesis even when seizures persist. The finding opens a potential therapeutic avenue: if follistatin can be maintained or replenished, the brain's natural regenerative capacity in the hippocampus might be protected.

The research was supported by the National Institutes of Health and conducted with access to specialized core facilities for neuroimaging and viral vector production. The work represents a shift in how researchers think about seizure-related cognitive decline—not simply as damage from electrical chaos, but as a disruption of a specific molecular pathway that can, in principle, be targeted independently of seizure control itself. Whether follistatin-based interventions will prove effective in human patients remains to be determined, but the pathway is now visible, and the mechanism is no longer a mystery.