Summary:
Researchers at Gladstone Institutes have decoded how parvalbumin (PV) interneurons generate gamma oscillations—the fast brain waves essential for attention and memory—by firing in precise, successive waves rather than all at once. In Alzheimer’s disease models, this coordinated turn-taking breaks down into hypersynchrony; however, restoring the sodium channel Nav1.1 resets cellular timing, repairs gamma rhythms, eliminates epileptic spikes, clears amyloid plaques, and rescues cognitive function.
Key Facts:
- Dynamic Turn-Taking Generates Gamma Waves: Using simultaneous in vivo two-photon imaging and electrical recordings in behaving mice, scientists discovered that PV interneurons generate 30–90 Hz gamma rhythms through a sequential relay: early responders fire strongly, subsequent groups fire progressively weaker, and one-third remain completely silent.
- Timing Breakdown in Alzheimer’s: In Alzheimer’s models, this delicate relay collapses, early cells become sluggish while late responders fire excessively, leading to abnormal hypersynchrony, faltering gamma rhythms, and epileptic-like network spikes.
- Nav1.1 Rescues Cognitive Health: Overexpressing the Nav1.1 sodium channel restored the natural firing sequence of PV cells, strengthened gamma oscillations, suppressed seizure-like spikes, reduced amyloid plaque burden, and extended lifespan and cognitive performance in mice.
Source: Gladstone Institutes
Whether focusing on a complex calculation, mastering a new skill, or retrieving an autobiographical memory, the mammalian brain relies on rapid, rhythmic electrical pulses known as gamma oscillations. Cycling between 30 and 90 times per second, these high-frequency background rhythms synchronize distant brain regions to facilitate high-level cognitive processing.
For decades, neuroscientists have recognized that gamma oscillations are severely degraded in patients with Alzheimer’s disease. Yet how individual cells naturally coordinate to generate these rhythms, and why that choreography collapses in disease, remained an enduring biological question.
Now, a study led by researchers at Gladstone Institutes, in collaboration with the Allen Institute and UTHealth Houston, has uncovered the precise cellular dynamics behind these cognitive waves.
Publishing in the journal Neuron, the research team revealed that specialized inhibitory cells called parvalbumin (PV) interneurons generate gamma rhythms by firing in precise, successive relays. Crucially, the researchers demonstrated that this relay breaks down in Alzheimer’s disease, and showed that restoring the sodium channel Nav1.1 resets cellular timing and rescues cognitive function.
Capturing Live Interneurons in Action
Previous research into gamma rhythms relied heavily on optogenetics, stimulating all PV interneurons simultaneously with light. While this proved that PV cells can drive gamma frequencies, mass stimulation obscured how single cells interact naturally in an awake, behaving animal.
“Turning on all the cells at once shows you what they can do, but not how they naturally work together or how they’re recruited to generate spontaneous gamma oscillations,” said lead author Keran Ma, PhD, who spearheaded the project as a postdoctoral scholar at Gladstone and is now an assistant professor at UTHealth Houston. “Until now, no one has actually been able to image these cells and look at gamma oscillations at the same time in an awake animal during natural behavior.”
To observe their natural behavior, the team combined high-speed in vivo electrical recordings with live optical imaging. Tracking mice running on treadmills, a behavior that naturally engages attention-related circuits, the researchers engineered PV interneurons to glow fluorescently each time they fired an action potential.
The imaging captured a dynamic cellular relay: during each gamma burst, PV cells fired in organized, progressive waves rather than a uniform pulse. The earliest responding cells exhibited powerful activity, followed by subsequent cohorts with progressively lower firing rates, while roughly 30% of the population remained completely quiet.
“The relationship between the PV cells and the gamma oscillations was much more dynamic and complex than we expected going into this,” said senior author Jorge J. Palop, PhD, an investigator at Gladstone Institutes. “Rather than all the cells contributing to the rhythm at once, each cell contributes for just a brief moment, and those small contributions add up to create the larger brain rhythm. It’s less like a military lockstep march and more like a flock of birds in the sky, each responding to the others, shifting turns and trajectories, yet together creating a remarkably coordinated pattern.”
The Collapse of Timing in Alzheimer’s
When the investigators examined mice genetically engineered to develop Alzheimer’s-like pathology, this coordinated relay was completely disrupted.
Instead of orderly turn-taking, early-responding PV cells became sluggish, late-stage cells fired excessively, and the inactive subset failed to stay silent. This loss of temporal segregation forced the cells into an abnormal hypersynchrony, firing simultaneously rather than sequentially, which paradoxically weakened the overall gamma rhythm.
“The important thing here is that more activity is not always going to produce better oscillations or better cognition,” Ma explained. “The dynamics of the cells are most important.”
This rhythmic breakdown provides a molecular explanation for a known clinical phenomenon: over 25% of Alzheimer’s patients exhibit subclinical epileptic-like brain activity. In the experimental models, epileptic spikes emerged directly after sudden drops in PV interneuron activity, illustrating how the breakdown of inhibitory timing destabilizes whole networks.
Rescuing Rhythms and Cognitive Function with Nav1.1
Looking for a way to repair the timing deficit, the team turned to Nav1.1, a voltage-gated sodium channel essential for generating fast electrical spikes in PV interneurons. Palop’s lab had previously demonstrated that Nav1.1 levels are significantly reduced in both Alzheimer’s mouse models and post-mortem human patient tissue.
To test whether replenishing the channel could fix the network, the researchers engineered Alzheimer’s mice to overexpress Nav1.1 within PV cells using cross-species viral delivery vehicles developed by Boaz P. Levi, PhD, and Jonathan T. Ting, PhD, of the Allen Institute.
The results were striking:
- Restored Cellular Rhythms: Elevated Nav1.1 restored normal sequential wave patterns in PV interneurons and boosted the power of gamma oscillations.
- Suppressed Network Hyperexcitability: Epileptic-like spikes were largely eliminated.
- Pathological and Behavioral Rescue: Treated mice showed marked reductions in amyloid plaque burden, improved performance on memory tasks, and significant extensions in lifespan.
“We still don’t know why interneuron dysfunction happens early in Alzheimer’s disease,” Ma noted. “But this is another study underscoring that a lot of the pathology of the disease could arise downstream of disrupted interneurons and the abnormal brain rhythms this disruption produces.”
The research team is now developing small-molecule Nav1.1 enhancers designed to selectively boost interneuron firing fidelity in humans, opening a therapeutic avenue to restore brain rhythms and protect against neurodegeneration.
Funding: The work was supported by the Ray and Dagmar Dolby Family Fund, the Cure Alzheimer’s Fund, the Simon Family Trust, the Alzheimer’s Association (24AARG-1247332), the Texas Alzheimer’s Research and Care Consortium (1271368), and the National Institutes of Health (AG094667, AG092683, AG082147, AG062629, AG073082, UG3/UH3 MH120095, R35 NS097976, R35 NS143067, RF1AG064926, K99/R00AG062776).
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this Alzheimer’s disease Research:
- Media Contact: Julie Langelier
- Source: Gladstone Institutes
- Image Credit: Image credited to Neuroscience News
- Original Research is Open Access: Neuron (Oct 1, 2026). “Parvalbumin cell state dynamics regulate gamma oscillations and are disrupted in Alzheimer’s disease.” Authors: Keran Ma, Kyerl Park, Patrick S. Honma, Yutong Zhang, Erica Brady, Yuechen Qiu, Ximena Opitz-Araya, Jonathan T. Ting, Boaz P. Levi, Katerina Akassoglou, and Jorge J. Palop.
- DOI: 10.1016/j.neuron.2026.09.025
Abstract
Parvalbumin cell state dynamics regulate gamma oscillations and are disrupted in Alzheimer’s disease
Gamma oscillations are fundamental for cognitive processing, but the cellular and circuit dynamics that generate them remain poorly defined.
Establishing a method for simultaneous calcium imaging and electrocorticography recordings in awake mice, we found that spontaneous gamma oscillations are accompanied by dynamic transitions between parvalbumin (PV) interneuron states.
Rather than acting as a uniformly synchronized population, PV interneurons showed sequential recruitment, transient inactivation, and frequent transitions between activity states, indicating the formation of dynamic functional networks.
In J20 Alzheimer’s disease mice, these state transitions became dysregulated, leading to abnormal PV recruitment, impaired coupling between PV activity and gamma oscillations, and network hyperexcitability. Increasing interneuron excitability through expression of the voltage-gated sodium channel Nav1.1 restored PV cell dynamics, gamma oscillations, and network stability.
These findings reveal dynamic PV cell states as an organizing feature of gamma oscillations and identify their disruption as a circuit mechanism of network dysfunction in Alzheimer’s disease.
