The Key Laboratory of Developmental Genes and Human Disease, Jiangsu Co-innovation Center of Neuroregeneration, Southeast University, Nanjing, China; Institute of Life Sciences, Collaborative Innovation Center for Brain Science, Southeast University, Nanjing, China
Celeste Leung
Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada
Yuehua Zhu
The Key Laboratory of Developmental Genes and Human Disease, Jiangsu Co-innovation Center of Neuroregeneration, Southeast University, Nanjing, China
Xingxiu Pan
The Key Laboratory of Developmental Genes and Human Disease, Jiangsu Co-innovation Center of Neuroregeneration, Southeast University, Nanjing, China
Junxia Qi
The Key Laboratory of Developmental Genes and Human Disease, Jiangsu Co-innovation Center of Neuroregeneration, Southeast University, Nanjing, China
Maria Morena
Hotchkiss Brain Institute, Cumming School of Medicine, Calgary, Canada; Department of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, Canada
Matthew N Hill
Hotchkiss Brain Institute, Cumming School of Medicine, Calgary, Canada; Department of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, Canada
Wei Xie
The Key Laboratory of Developmental Genes and Human Disease, Jiangsu Co-innovation Center of Neuroregeneration, Southeast University, Nanjing, China; Institute of Life Sciences, Collaborative Innovation Center for Brain Science, Southeast University, Nanjing, China
Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada
PAK1 inhibitors are known to markedly improve social and cognitive function in several animal models of brain disorders, including autism, but the underlying mechanisms remain elusive. We show here that disruption of PAK1 in mice suppresses inhibitory neurotransmission through an increase in tonic, but not phasic, secretion of endocannabinoids (eCB). Consistently, we found elevated levels of anandamide (AEA), but not 2-arachidonoylglycerol (2-AG) following PAK1 disruption. This increased tonic AEA signaling is mediated by reduced cyclooxygenase-2 (COX-2), and COX-2 inhibitors recapitulate the effect of PAK1 deletion on GABAergic transmission in a CB1 receptor-dependent manner. These results establish a novel signaling process whereby PAK1 upregulates COX-2, reduces AEA and restricts tonic eCB-mediated processes. Because PAK1 and eCB are both critically involved in many other organ systems in addition to the brain, our findings may provide a unified mechanism by which PAK1 regulates these systems and their dysfunctions including cancers, inflammations and allergies.
