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.

Cortex-restricted deletion of Foxp1 impairs barrel formation and induces aberrant tactile responses in a mouse model of autism.

BACKGROUND: Many children and young people with autism spectrum disorder (ASD) display touch defensiveness or avoidance (hypersensitivity), or engage in sensory seeking by touching people or objects (hyposensitivity). Abnormal sensory responses have also been noticed in mice lacking ASD-associated genes. Tactile sensory information is normally processed by the somatosensory system that travels along the thalamus to the primary somatosensory cortex. The neurobiology behind tactile sensory abnormalities, however, is not fully understood. METHODS: We employed cortex-specific Foxp1 knockout (Foxp1-cKO) mice as a model of autism in this study. Tactile sensory deficits were measured by the adhesive removal test. The mice's behavior and neural activity were further evaluated by the whisker nuisance test and c-Fos immunofluorescence, respectively. We also studied the dendritic spines and barrel formation in the primary somatosensory cortex by Golgi staining and immunofluorescence. RESULTS: Foxp1-cKO mice had a deferred response to the tactile environment. However, the mice exhibited avoidance behavior and hyper-reaction following repeated whisker stimulation, similar to a fight-or-flight response. In contrast to the wild-type, c-Fos was activated in the basolateral amygdala but not in layer IV of the primary somatosensory cortex of the cKO mice. Moreover, Foxp1 deficiency in cortical neurons altered the dendrite development, reduced the number of dendritic spines, and disrupted barrel formation in the somatosensory cortex, suggesting impaired somatosensory processing may underlie the aberrant tactile responses. LIMITATIONS: It is still unclear how the defective thalamocortical connection gives rise to the hyper-reactive response. Future experiments with electrophysiological recording are needed to analyze the role of thalamo-cortical-amygdala circuits in the disinhibiting amygdala and enhanced fearful responses in the mouse model of autism. CONCLUSIONS: Foxp1-cKO mice have tactile sensory deficits while exhibit hyper-reactivity, which may represent fearful and emotional responses controlled by the amygdala. This study presents anatomical evidence for reduced thalamocortical connectivity in a genetic mouse model of ASD and demonstrates that the cerebral cortex can be the origin of atypical sensory behaviors.

Unilateral cerebral ischemia induces morphological changes in the layer V projection neurons of the contralateral hemisphere.

Decreased blood flow to the brain causes stroke and damage to neuronal networks. Neuronal damage occurs not only in the infarct core but also in areas away from the infarcts. This study was aimed to assess alterations of the cortical projection neurons that were distantly connected with the infarcts. Unilateral cortical ischemia was generated by middle cerebral artery occlusion in the right somatosensory cortex. Pre-labeled thalamocortical neurons disappeared, whereas contralateral callosal projection neurons survived 48 h post-ischemia. The unilateral ischemia increased the total length, segment length and the spine volume of dendrites from layer V callosal neurons in the homotopic cortex of the contralateral hemisphere. The morphological remolding of the contralateral cortical neurons cannot be reproduced by the spinal cord hemisection that cuts axons of corticospinal projection neurons of layer V. The data suggest that the retrograde degeneration of axons may not account for the early morphological changes in the contralateral cortex. We hypothesize that the loss of innervations from the ischemic cortex may bring in adaptive changes to the connected neurons, and adult cortical neurons can adjust their morphology to meet the reduction of synaptic inputs. This study may improve our understanding of the re-organization of cortical circuits following focal cerebral ischemia and help the development of new treatments designed to minimize the disability associated with stroke.

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

Efficient 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.