Regulation of PV interneuron plasticity by neuropeptide-encoding genes

• 成果类型: Article; Early Access
• 署名作者: Selten, Martijn; Bernard, Clemence; Mukherjee, Diptendu; Hamid, Fursham; Hanusz-Godoy, Alicia; Oozeer, Fazal; Zimmer, Christoph; Marin, Oscar
• 署名单位: University of London; King's College London; University of London; King's College London; University of Exeter
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-08933-z
• 发表日期: 2025-04-30
• 关键词: disinhibitory microcircuit; gabaergic interneurons; synaptic plasticity; inhibitory neurons; mechanisms; excitation; expression; synapses; distinct; vgf

摘要

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 function1, 2-3. 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 cells4, 5, 6, 7-8, 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.