Contactin-associated protein-like 4 (Cntnap4) is critical for GABAergic transmission in the brain. Impaired Cntnap4 function is implicated in neurological disorders, such as autism; however, the role of Cntnap4 on memory processing is poorly understood. Here, we demonstrate that hippocampal deficiency in female mice manifests as impaired cognitive function and synaptic plasticity. The underlying mechanisms may involve effects on the pro-inflammatory response resulting in dysfunctional GABAergic transmission and activated tryptophan metabolism. To efficiently and accurately inhibit the pro-inflammatory reaction, we established a biomimetic microglial nanoparticle strategy to deliver FDA-approved PLX3397 (termed MNPs@PLX). We show MNPs@PLX successfully penetrates the blood brain barrier and facilitates microglial-targeted delivery of PLX3397. Furthermore, MNPs@PLX attenuates cognitive decline, dysfunctional synaptic plasticity, and pro-inflammatory response in female heterozygous knockout mice. Together, our findings show loss of causes pro-inflammatory cognitive decline that is effectively prevented by supplementation with microglia-specific inhibitors; thus validating the targeting of microglial function as a therapeutic intervention in neurocognitive disorders.