Autism spectrum disorders (ASDs) are synaptopathies, caused by misconnected neural networks during brain development. Genes encoding proteins associated with the excitatory glutamate receptor complex are a hot spot for ASD-associated mutations. However, alterations of both excitatory and inhibitory synapses, as well as differences in the direction of the changes in young versus old mice, have been described in genetic mouse models of ASDs. Thus, the pathophysiology of ASDs appears multifaceted, including both primary defects and likely secondary homeostatic adjustments, which complicates the identification of core, primary defects. With the goal of identifying such primary defects, Oliver Schlüter and colleagues at the University of Pittsburgh will focus on assessing ASD-associated proteins in the glutamate receptor complex and their role in neurocircuit development.

Several ASD-associated proteins bind to the signaling scaffold PSD-95 in the glutamate receptor complex. Schlüter’s team previously reported that progressive PSD-95-based silent synapse maturation closes a critical period during neural development¹. Silent synapses contain NMDA receptors without stable AMPA receptors. Relevant experience turns silent synapses into fully transmitting ones through stable AMPA receptor incorporation; such a process is thought to be instrumental during neural network refinement of principal neurons.

Based on the significant role of circuit refinement and the glutamate receptor complex in the etiology of ASD, Schlüter’s team will assess whether aberrations in silent synapse-based developmental circuit refinement are a common phenotype in genetic mouse models of ASD and, thus, may represent one of the initial changes leading to the pathophysiology of ASD. To do so, Schlüter’s team is assessing the developmental profile of silent synapses in three different mouse models for ASD — Shank3, Syngap1 and Nlgn3 hetero- or homozygous knockout mice. Taken together, this project will reveal whether ASD-associated proteins of the glutamate receptor complex have a role in developmental silent synapse maturation, with the aim of identifying a common starting point for the pathophysiology of ASDs as a critical period disorder.