Regulation of neural circuit development by cadherin-11 provides implications for autism

Jeannine A. Frei, Robert F. Niescier, Morgan S. Bridi, Madel Durens, Jonathan E. Nestor, Michaela B.C. Kilander, Xiaobing Yuan, Derek M. Dykxhoorn, Michael W. Nestor, Shiyong Huang, Gene J. Blatt, Yu Chih Lin

Research output: Contribution to journalArticlepeer-review

Abstract

Autism spectrum disorder (ASD) is a neurologic condition characterized by alterations in social interaction and com-munication, 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 en-riched 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, but downregulated CDH11. We used Cdh11 knock-out (KO) 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 complex-ity along with altered neuronal and synaptic activity. Similar to the expression profiles in human tissue, levels of cad-herin-8 were significantly elevated in Cdh11 KO brains. Additionally, excitatory synaptic markers neuroligin-1 and postsynaptic density (PSD)-95 were both increased. Together, these results strongly suggest that cadherin-11 is in-volved in regulating the development of neuronal circuitry and that alterations in the expression levels of cadherin-11 may contribute to the etiology of autism.

Original languageEnglish (US)
Article numberENEURO.0066-21.2021
JournaleNeuro
Volume8
Issue number4
DOIs
StatePublished - 2021

Keywords

  • Autism spectrum disorder
  • Cadherin-11
  • Cadherin-8
  • Cdh11 knock-out mice
  • Neural circuit formation
  • Neuroligin-1

ASJC Scopus subject areas

  • Neuroscience(all)

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