Microglial targeted therapy relieves cognitive impairment caused by Cntnap4 deficiency
Wenlong Zhang,
Huaqing Chen,
Liuyan Ding,
Jie Huang,
Mengran Zhang,
Yan Liu,
Runfang Ma,
Shaohui Zheng,
Junwei Gong,
Juan C. Piña‐Crespo,
Yunlong Zhang
Affiliations
Wenlong Zhang
Department of Neurology The First Affiliated Hospital of Guangzhou Medical University Guangzhou China
Huaqing Chen
Shenzhen Key Laboratory of Gene and Antibody Therapy Center for Biotechnology and Biomedicine State Key Laboratory of Chemical Oncogenomics State Key Laboratory of Health Sciences and Technology Institute of Biopharmaceutical and Health Engineering Shenzhen International Graduate School Tsinghua University Shenzhen China
Liuyan Ding
Department of Neurology The First Affiliated Hospital of Guangzhou Medical University Guangzhou China
Jie Huang
Key Laboratory of Neurological Function and Health School of Basic Medical Sciences Guangzhou Medical University Guangzhou China
Mengran Zhang
Key Laboratory of Neurological Function and Health School of Basic Medical Sciences Guangzhou Medical University Guangzhou China
Yan Liu
School of Traditional Chinese Medicine Jinan University Guangzhou China
Runfang Ma
Key Laboratory of Neurological Function and Health School of Basic Medical Sciences Guangzhou Medical University Guangzhou China
Shaohui Zheng
Key Laboratory of Neurological Function and Health School of Basic Medical Sciences Guangzhou Medical University Guangzhou China
Junwei Gong
Key Laboratory of Neurological Function and Health School of Basic Medical Sciences Guangzhou Medical University Guangzhou China
Juan C. Piña‐Crespo
Degenerative Diseases Program Center for Genetic Disorders and Aging Research Sanford Burnham Prebys Medical Discovery Institute La Jolla California USA
Yunlong Zhang
Key Laboratory of Neurological Function and Health School of Basic Medical Sciences Guangzhou Medical University Guangzhou China
Abstract 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.
