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Organization of mammalian inhibitory synapses is thought to be crucial for normal brain functions, but the underlying molecular mechanisms have remained largely undefined. IQSEC3, a guanine nucleotide exchange factor for ADP-ribosylation factor (ARF-GEF), is a component of γ-aminobutyric acid-producing (GABAergic) synapses that directly interacts with gephyrin. Here, we show that IQSEC3 (IQ motif and Sec7 domain 3) acts in a synaptic activity-dependent manner to regulate GABAergic synapse development in vivo. We found that Npas4 (neuronal PAS domain protein 4), a transcription factor that controls the number of GABAergic synapses formed on excitatory neurons, directly binds to the promoter of Iqsec3 and regulates its transcription. Moreover, IQSEC3 functions downstream of Npas4 to orchestrate GABAergic synapse development. Strikingly, injection of mice with kainic acid (KA) induced Npas4 upregulation and concurrently increased IQSEC3 protein expression levels, especially in somatostatin (SST)-positive GABAergic interneurons in the hippocampal CA1 stratum oriens layer, which are blunted in Npas4 knockout (KO) mice. Furthermore, expression of wild-type (WT) IQSEC3, but not a dominant-negative (DN) ARF-GEF–inactive mutant, normalized the altered GABAergic synaptic transmission and formation on dendrites, but not the soma, of Npas4-deficient CA1 neurons. Lastly, expression of IQSEC3 WT, but not IQSEC3 DN, rescued the altered depressive behavior observed in mice in which Npas4 expression is disrupted in the CA1 region of the hippocampus. Collectively, our results suggest that IQSEC3 is a key GABAergic …