Inhibition of Foxp4 Disrupts Cadherin-based Adhesion of Radial Glial Cells,Leading to Abnormal Differentiation and Migration of Cortical Neurons in Mice

Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders(NDDs)that exhibit delayed speech development,intellectual disability,and congenital abnormalities.The etiology of NDDs is unclear.Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells(RGCs),respectively,in the mouse neocortex during early gestation.Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone(VZ).Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ.The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs.The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions,the loss of which leads to periventricular heterotopias.We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.

High-Throughput Automatic Training System for Spatial Working Memory in Free-Moving Mice

Effcient behavioral assays are crucial for understanding the neural mechanisms of cognitive functions.Here, we designed a high-throughput automatic training system for spatial cognition(HASS) for free-moving mice.Mice were trained to return to the home arm and remain there during a delay period. Software was designed to enable automatic training in all its phases, including habituation, shaping, and learning. Using this system, we trained mice to successfully perform a spatially delayed nonmatch to sample task, which tested spatial cognition,working memory, and decision making. Performance depended on the delay duration, which is a hallmark of working memory tasks. The HASS enabled a human operator to train more than six mice simultaneously with minimal intervention, therefore greatly enhancing experimental efficiency and minimizing stress to the mice.Combined with the optogenetic method and neurophysiological techniques, the HASS will be useful in deciphering the neural circuitry underlying spatial cognition.