Enhancing neurogenesis within the hippocampal dentate gyrus (DG) is critical for maintaining brain development and function in many neurological diseases. However, the neural mechanisms underlying neurogenesis in depression remain unclear. Here, we show that microglia transfer a microglia-enriched microRNA, miR-146a-5p, which then inhibits neurogenesis in depression via its capacity to secrete exosomes to DG regions. Overexpression of miR-146a-5p in DG regions suppresses neurogenesis and spontaneous discharge of excitatory neurons by directly targeting Kruppel-like factor 4 (KLF4). Down-regulation of miR-146a-5p expression, ameliorates adult neurogenesis deficits in DG regions and depression-like behaviors in rats. Intriguingly, circular-RNA ANKS1B acts as a miRNA sponge for miR-146a-5p to mediate posttranscriptional regulation of KLF4 expression. Collectively, these results indicate that miR-146a-5p can function as a critical factor regulating neurogenesis under conditions of pathological processes resulting from depression and suggest that microglial exosomes generate new cross-talk channels between glial cells and neurons.