The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition

The transcription factor NPAS4 enables neurons to distinguish synaptic inputs received at their soma or dendrites; sensory stimulation increases NPAS4 which promotes inhibitory synapses on the soma and destabilizes inhibitory synapses on the dendrites. Individual neurons distinguish synaptic inputs received at their soma and dendrites, but how behaviour may affect their balance has been unclear. Now Michael Greenberg and colleagues show that mouse hippocampus neurons respond to sensory enrichment with increased levels of the transcription factor NPAS4 and its target-gene product, brain derived neurotrophic factor (BDNF), which then promotes inhibitory synapses on the cell body while destabilizing those on dendrites. Thus individual neurons respond to sensory stimulation by redrawing the map of their inhibitory inputs, restricting their somatic output while promoting plasticity at their dendrites. A heterogeneous population of inhibitory neurons controls the flow of information through a neural circuit1,2,3. Inhibitory synapses that form on pyramidal neuron dendrites modulate the summation of excitatory synaptic potentials4,5,6 and prevent the generation of dendritic calcium spikes7,8. Precisely timed somatic inhibition limits both the number of action potentials and the time window during which firing can occur8,9. The activity-dependent transcription factor NPAS4 regulates inhibitory synapse number and function in cell culture10, but how this transcription factor affects the inhibitory inputs that form on distinct domains of a neuron in vivo was unclear. Here we show that in the mouse hippocampus behaviourally driven expression of NPAS4 coordinatesthe redistribution of inhibitory synapses made onto a CA1 pyramidal neuron, simultaneously increasing inhibitory synapse number on the cell body while decreasing the number of inhibitory synapses on the apical dendrites. This rearrangement of inhibition is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (Bdnf), which specifically regulates somatic, and not dendritic, inhibition. These findings indicate that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.