Frei_2021_eNeuro__

Autism spectrum disorder (ASD) is a neurological condition characterized by alterations in social interaction and communication, and restricted and/or repetitive behaviors. The classical type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and in autism-specific human tissue. In mice, expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in the cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Both cadherins were expressed in synaptic compartments but only cadherin-8 associated with the excitatory synaptic marker neuroligin-1. Induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed upregulated CDH8 expression levels while CDH11 expression levels were downregulated. We used Cdh11 knockout mice of both sexes to analyze the function of cadherin-11, which could help explain phenotypes observed in autism. Cdh11(-/-) hippocampal neurons exhibited increased dendritic complexity along with altered neuronal and synaptic activity. Similar to the expression profiles in human tissue, levels of cadherin-8 were significantly elevated in Cdh11 knockout brains. Additionally, excitatory synaptic markers neuroligin-1 and PSD-95 were both increased. Together, these results strongly suggest that cadherin-11 is involved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-11 may contribute to the etiology of autism.Significance StatementAutism is a neurodevelopmental condition with high genetic and phenotypic heterogeneity. Multiple genes have been implicated in autism, including the cadherin superfamily of adhesion molecules, cadherin-8 and cadherin-11. This study first characterizes the expression profiles of cadherin-8 and cadherin-11 to understand the potential roles they play in the development of neurons. The study further describes novel contributions of cadherin-11 in neural circuit formation. Loss of cadherin-11 in mice results in altered levels of several synaptic proteins, including PSD-95, neuroligin-1, and cadherin-8, and changes the morphology and activity of excitatory neurons. The levels of cadherin-8 and cadherin-11 in human cells of autistic individuals are both altered, strengthening the hypothesis that these two cadherins may involve in aspects of autism etiology.