Regulation 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.