Pyramidal neurons proportionately alter cortical interneuron subtypes
Article Date: 21 January 2026
Article URL: https://www.nature.com/articles/s41586-025-09996-8
Article Image: https://www.nature.com/articles/s41586-025-09996-8/figures/1
Summary
This Nature paper reports that cortical pyramidal (excitatory) neuron subtypes actively shape the proportions, laminar distributions and transcriptomic states of major inhibitory interneuron families (particularly PVALB and SST subtypes) during postnatal development. Using multi-modal single-cell and spatial approaches (snRNA-seq, MERFISH, Slide-seq), combined with genetic manipulations (Fezf2 knockout to alter pyramidal subtype composition, Bax removal to block interneuron death, and activity perturbations using Kir2.1/TeNT), the authors show that changes to pyramidal neuron populations lead to predictable, proportional shifts in interneuron subtype composition and placement. These effects emerge after birth (postnatal day 2 onward), involve both survival and transcriptional plasticity, and are linked to candidate signalling pathways (including Wnt5a among others) that may mediate communication from pyramidal cells to interneurons.
Key Points
- Altering pyramidal neuron subtype composition (Fezf2 KO) redistributes and changes proportions of PVALB and SST interneuron subtypes, notably in deep cortical layers.
- High-resolution spatial transcriptomics (MERFISH, Slide-seq) plus snRNA-seq allowed mapping of interneuron subtype identity, laminar position and region-specific differences across motor, somatosensory and visual cortex.
- Interneuron proportion changes appear after P2 and arise via both altered survival (tested via Bax deletion) and transcriptomic plasticity of remaining interneurons.
- Reducing pyramidal neuron activity (Kir2.1, TeNT) and specific genetic manipulations produced transcriptomic shifts in interneurons, suggesting activity-dependent and molecular signalling mechanisms.
- Bioinformatic ligand–receptor screens identified candidate pyramidal-to-interneuron signals (Wnt5a highlighted) that could mediate subtype-specific effects.
- The study combines intersectional genetics, viral labelling, RNAscope and rigorous statistical models to validate spatial and proportional changes across genotypes and ages.
Content summary
The authors mapped PVALB and SST interneuron diversity across cortical regions and layers, showing stereotyped laminar distributions and region-specific subtype proportions. By perturbing pyramidal neuron identity (Fezf2 loss) they observed an upward laminar shift and subtype proportion changes among interneurons in affected areas. Complementary experiments limiting interneuron apoptosis (Bax conditional removal) and altering pyramidal neuron activity further dissected mechanisms: some subtype changes depend on altered survival, while others reflect transcriptomic reprogramming of interneurons. Spatial and temporal analyses indicate these changes arise postnatally (after P2). A candidate list of ligand–receptor interactions from pyramidal cells to interneurons was generated, with Wnt5a among validated regionally expressed cues. Overall, the work argues that excitatory neuron subtype composition is a key upstream determinant of inhibitory circuit makeup during cortical assembly.
Context and relevance
Excitatory–inhibitory balance and precise interneuron placement are foundational for cortical computation and are implicated in neurodevelopmental disorders. This paper advances the idea that excitatory (pyramidal) neuron diversity doesn’t just wire with interneurons passively — it actively instructs which interneuron subtypes persist, where they reside and how they express key genes. The combination of spatial transcriptomics and causal manipulations strengthens claims about mechanism and timing, linking cell-type composition, survival pathways and candidate molecular signals. For researchers studying cortical development, circuit assembly, or disease models where excitatory neuron identity is perturbed, these results provide new hypotheses and datasets (GEO accession GSE272706 and Single Cell Portal SCP2716) to explore.
Why should I read this?
Quick and messy take: if you care about how the cortex gets its mix of inhibitory cells — stop skimming and read this. The team did the heavy lifting with spatial single-cell maps and real genetic tinkering to show pyramidal cells actively set the interneuron menu. It’s the kind of paper that saves you time: instead of guessing whether interneuron differences are intrinsic or imposed, this shows pyramidal identity does a lot of the ordering — and gives you candidate signals to test next.
Author style
Punchy: the study is methodologically rigorous and directly relevant — it reshapes how we think about hierarchical control in cortical development. If your work touches cortical circuit composition, development or disease, the detailed methods, datasets and candidate ligand–receptor lists here are worth diving into.