Rac-GEF signaling in dendritic spines

点击翻译按钮获取中文摘要

ABSTRACT The number, size, and plasticity of spiny excitatory synapses underlies connectivity in neuronal circuits, and their alterations are central to the pathogenesis of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability (ID), and fragile X syndrome (FXS). Our long-term goals is to uncover the biological functions of Rho-like small GTPase pathways at central excitatory synapses and their contributions to NDDs. Rho GTPases, including Rac1, play key role in spiny excitatory synapse formation, plasticity, neurotransmission, circuit development, and behavior. Conversely, alterations in Rho GTPase signaling occur in many NDDs, including ASD, ID, and FXS. Notably, overactivation of this pathway occurs in FXS model mice (Fmr1 KO), as well as in patients with gain-of-function mutations in the TRIO, RAC1, and PAK1 genes, and is associated with synaptic hyperconnectivty, hyperexcitability, ASD, ID, and epilepsy. Hence detailed knowledge of the regulation of Rho GTPases and ability to modulate them would have broad implications for understanding brain function and dysfunction in NDDs. Rho GTPases are directly activated by guanine-nucleotide exchange factors (GEFs). The paralog GEFs kalirin and Trio are important regulators of neuronal connectivity, and are dysregulated in several NDDs. Both proteins directly activate Rac1 and subsequently, p21-activated kinase (Pak), which also play key roles in brain development, plasticity, and NDDs. Notably, inhibition of Rac1 and Pak rescued phenotypes in Fmr1 KO mice. Here we outline a set of experiments designed to determine the role of the kalirin/Trio->Rac1->Pak axis in basal brain function and in preclinical models of NDDs characterized by excessive synaptic connectivity (hyperconnectivity). Specifically, we will test whether inhibition of the kalirin/Trio->Rac1->Pak axis to reverse structural, functional, and behavioral deficits in several mouse models relevant for NDDs. We will pursue the following Specific Aims: 1) To characterize the biological effects of kalirin/Trio inhibition in basal brain function in mice. 2) To determine the effects of genetic deletion of kalirin and Trio on disease-relevant phenotypes in mouse models of NDD with synaptic hyperconnectivity. 3) To compare the biological effects of kalirin/Trio inhibition with that of known Rac1 and Pak inhibitors in mouse models of NDD with synaptic hyperconnectivity.