Hippocampal Cntnap4 deficiency was associated with cognitive impairment via inducing pro-inflammatory response in females. A biomimetic microglial nanoparticle system (MNPs@PLX) was established for precise microglial delivery of FDA-approved PLX3397 to attenuate cognitive decline, dysfunctional synaptic plasticity, and pro-inflammatory response in female heterozygous Cntnap4 knockout mice. This study indicates that microglial supplementation of PLX3397 may serve as an intervention for cognitive impairment.
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 Cntnap4 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 Cntnap4 knockout mice. Together, our findings show loss of Cntnap4 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.
Wenlong Zhang†, Huaqing Chen†, Liuyan Ding†, Jie Huang†, Mengran Zhang†, Yan Liu, Runfang Ma, Shaohui Zheng, Junwei Gong, Juan C. Piña-Crespo, Yunlong Zhang*
How to cite:
W. Zhang, H. Chen, L. Ding, J. Huang, M. Zhang, Y. Liu, R. Ma, S. Zheng, J. Gong, J. C. Piña-Crespo, Y. Zhang, Exploration 2023, 20220160.