Cortexa Weekly— June 9th 2025
Cortexa Progress
People First, Then Paperwork
This week was all about connections. Cortexa initiated conversations with several consultants and foundations who align with our urgency and vision. The science is solid; now we’re building the network that’ll carry it forward. Trust, relationships, and strategic alignment—those are the multipliers we’re hunting.
Research Spotlight
Study Title: Calcium‑permeable AMPA receptors govern PV neuron feature selectivity
Journal: Nature Medicine (2024)
URL: https://www.nature.com/articles/s41586-024-08027-2#Sec7
CP-AMPARs Tune—or Blur—the Brain’s Signal
This paper highlights a powerful mechanism in cortical PV interneurons: when these inhibitory neurons express CP-AMPARs—a special type of AMPA receptor that lacks the GluA2 subunit—they show low stimulus feature selectivity. In other words, they respond to a broader range of inputs, making their inhibition less precise. But when CP-AMPARs are removed (by restoring GluA2), these neurons become much more selective, responding more accurately to specific stimuli like visual orientation or spatial position.
Most notably, adjusting CP-AMPAR levels didn’t change the wiring or strength of the connections—it changed how those neurons interpret and process information. That’s the big takeaway: we may be able to tune brain function by modulating receptor composition, not the network itself.
For readers newer to neuroscience: AMPA receptors are like the communication lines between neurons—they help pass messages fast, almost like tossing notes in class. Normally, these receptors don’t let calcium through. But CP-AMPARs do, and that extra calcium can shift how a neuron behaves.This aligns beautifully with our model at Cortexa: calcium-permeable AMPA receptors (CP-AMPARs) are central to disease progression. Whether through faulty editing (like loss of ADAR2) or TARP dysregulation, the result is the same: calcium overload, mitochondrial damage, and motor neuron death. The Japanese study validates the upstream hypothesis we've been building around for months.
Here’s the big picture: excitatory neurons act like the gas pedal in your brain—they drive activity and push signals forward. Inhibitory neurons, like PV interneurons, are the brakes. They help calm things down, fine-tune timing, and keep circuits stable. While inhibitory neurons—including PV interneurons—do express CP-AMPARs under normal physiological conditions, this study suggests that elevated or unregulated CP-AMPAR activity can disrupt their precision. It's like their braking system gets noisy and imprecise—making it harder to filter and sharpen the signal.
What I’m Thinking About
This study was also a major reassurance for us. One of my biggest concerns has always been the potential for off-target effects—what happens when we reduce CP-AMPARs in cells that might actually rely on them for proper function? Could we blunt signal processing or interfere with essential neural computation? This paper answered that fear head-on: removing CP-AMPARs sharpened selectivity rather than degrading function. It suggests that far from being a blunt tool, modulating CP-AMPARs could enhance performance where it matters most.
Why It Matters to Cortexa
Calcium influx as amplifier—or vulnerability: CP‑AMPARs let calcium flow into inhibitory cells—if we regulate them, we may influence disease pathways beyond excitatory neurons.
A new axis of therapeutic precision: Modulating CP‑AMPARs gives us a potential tool to finely tune circuit dynamics—precisely targeting motor network dysfunction in ALS.
Functional overlap: While we’re not using RNA editing, this paper reinforces the importance of reducing CP‑AMPAR formation—something we’re tackling through small molecule strategies targeting GluA2-lacking AMPARs in excitatory neurons, with implications now extending to inhibitory circuits as well.
Neurodegeneration isn’t just neuron death—it’s a disruption of tuning. This paper shows that calcium-sensitive plasticity shapes that tuning and gives us a precise axis to adjust—and therefore protect—network function.
Join the Movement
More to come next week. If you know someone who cares about science, startups, or finding real answers to ALS, share this with them. Cortexa isn’t just a company—it’s a mission grounded in hard data, propelled by urgency, and carried by people who refuse to settle for the status quo. Every experiment, every conversation, every forward step brings us closer to shifting the balance.
Whether you’re here for the science, the story, or the fight—thanks for walking it with us.
