biostudies-literatureSelten MEuropean Research Council173-181https://www.ebi.ac.uk/biostudies/studies/S-EPMC12222018biostudies-literatureUnknown643(8070)Neuronal activity must be regulated in a narrow permissive band for the proper operation of neural networks. Changes in synaptic connectivity and network activity-for example, during learning-might disturb this balance, eliciting compensatory mechanisms to maintain network function^1-3. In the neocortex, excitatory pyramidal cells and inhibitory interneurons exhibit robust forms of stabilizing plasticity. However, although neuronal plasticity has been thoroughly studied in pyramidal cells^4-8, little is known about how interneurons adapt to persistent changes in their activity. Here we describe a critical cellular process through which cortical parvalbumin-expressing (PV⁺) interneurons adapt to changes in their activity levels. We found that changes in the activity of individual PV⁺ interneurons drive bidirectional compensatory adjustments of the number and strength of inhibitory synapses received by these cells, specifically from other PV⁺ interneurons. High-throughput profiling of ribosome-associated mRNA revealed that increasing the activity of a PV⁺ interneuron leads to upregulation of two genes encoding multiple secreted neuropeptides: Vgf and Scg2. Functional experiments demonstrated that VGF is critically required for the activity-dependent scaling of inhibitory PV⁺ synapses onto PV⁺ interneurons. Our findings reveal an instructive role for neuropeptide-encoding genes in regulating synaptic connections among PV⁺ interneurons in the adult mouse neocortex.NatureRegulation of PV interneuron plasticity by neuropeptide-encoding genes.PMC12222018787355Oozeer FHamid FSelten MBernard CZimmer CHanusz-Godoy AMukherjee DMarin OfalseRegulation of PV interneuron plasticity by neuropeptide-encoding genes.Neuronal activity must be regulated in a narrow permissive band for the proper operation of neural networks. Changes in synaptic connectivity and network activity-for example, during learning-might disturb this balance, eliciting compensatory mechanisms to maintain network function^1-3. In the neocortex, excitatory pyramidal cells and inhibitory interneurons exhibit robust forms of stabilizing plasticity. However, although neuronal plasticity has been thoroughly studied in pyramidal cells^4-8, little is known about how interneurons adapt to persistent changes in their activity. Here we describe a critical cellular process through which cortical parvalbumin-expressing (PV⁺) interneurons adapt to changes in their activity levels. We found that changes in the activity of individual PV⁺ interneurons drive bidirectional compensatory adjustments of the number and strength of inhibitory synapses received by these cells, specifically from other PV⁺ interneurons. High-throughput profiling of ribosome-associated mRNA revealed that increasing the activity of a PV⁺ interneuron leads to upregulation of two genes encoding multiple secreted neuropeptides: Vgf and Scg2. Functional experiments demonstrated that VGF is critically required for the activity-dependent scaling of inhibitory PV⁺ synapses onto PV⁺ interneurons. Our findings reveal an instructive role for neuropeptide-encoding genes in regulating synaptic connections among PV⁺ interneurons in the adult mouse neocortex.2025-01-01T00:00:00Z2025 Jul2026-06-02T06:01:12.439Z2026-04-15T03:10:02.143ZS-EPMC122220184030754710.1038/s41586-025-08933-z