Altered Expression of Cadherin-8 and Cadherin-11 in Neural Circuit Development: Implications for Autism

Autism spectrum disorder (ASD) is a neurological condition characterized by difficulties in social interaction, communication, and behavior. 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 analyzed their functions using knockout mice. Expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Cadherin-8 preferentially localized to excitatory synapses where it interacted with neuroligin-1. Levels of cadherin-8, neuroligin-1, and PSD-95 were all significantly increased in knockout brains. Additionally, hippocampal neurons exhibited increased dendritic complexity along with altered neuronal and synaptic activity. Similar to the expression profiles in knockout mice, induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed elevated CDH8 expression levels while CDH11 expression levels were decreased. Together, these results strongly suggest that cadherin-8 and cadherin-11 are involved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-8 and cadherin-11 may contribute to the etiology of autism.