Mutations and modeling of the chromatin remodeler CHD8 define an emerging autism etiology

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder with a strong but complex genetic component. Recent family based exome-sequencing strategies have identified recurrent de novo mutations at specific genes, providing strong evidence for ASD risk, but also highlighting the extreme genetic heterogeneity of the disorder. However, disruptions in these genes converge on key molecular pathways early in development. In particular, functional enrichment analyses have found that there is a bias towards genes involved in transcriptional regulation, such as chromatin regulators. Here we review recent genetic, animal model, co-expression network, and functional genomics studies relating to the high confidence ASD risk gene, CHD8. CHD8 a chromatin remodeling factor, may serve as a master regulator of a common ASD etiology. Individuals with a CHD8 mutation show an ASD subtype that includes similar physical characteristics, such as macrocephaly and prolonged GI problems including recurrent constipation. Similarly, animal models of CHD8 disruption exhibit enlarged head circumference and reduced gut motility phenotypes. Systems biology approaches suggest CHD8 and other candidate ASD risk genes are enriched during mid-fetal development, which may represent a critical time window in ASD etiology. Transcription profiles from cell and primary tissue models of early development indicate that CHD8 may also positively regulate other candidate ASD risk genes through both direct and indirect means. However continued study is needed to elucidate the mechanism of regulation as well as identify which CHD8 targets are most relevant to ASD risk. Overall, these initial studies suggest the potential for common ASD etiologies and the development of personalized treatments in the future

Multiple Representations of Space by the Cockroach, Periplaneta americana

When cockroaches are trained to a visual–olfactory cue pairing using the antennal projection response (APR), they can form different memories for the location of a visual cue. A series of experiments, each examining memory for the spatial location of a visual cue, were performed using restrained cockroaches. The first group of experiments involved training cockroaches to associate a visual cue (CS—green LED) with an odor cue (US) in the presence or absence of a second visual reference cue (white LED). These experiments revealed that cockroaches have at least two forms of spatial memory. First, it was found that during learning, the movements of the antennae in response to the odor influenced the cockroaches’ memory. If they use only one antenna, cockroaches form a memory that results in an APR being elicited to the CS irrespective of its location in space. When using both antennae, the cockroaches resulting memory leads to an APR to the CS that is spatially confined to within 15° of the trained position. This memory represents an egocentric spatial representation. Second, the cockroaches simultaneously formed a memory for the angular spatial relationships between two visual cues when trained in the presence of a second visual reference cue. This training provided the cockroaches an allocentric representation or visual snapshot of the environment. If both egocentric and the visual snapshot were available to the cockroach to localize the learned cue, the visual snapshot determined the behavioral response in this assay. Finally, the split-brain assay was used to characterize the cockroach’s ability to establish a memory for the angular relationship between two visual cues with half a brain. Split-brain cockroaches were trained to unilaterally associate a pair of visual cues (CS—green LED and reference—white LED) with an odor cue (US). Split-brain cockroaches learned the general arrangement of the visual cues (i.e., the green LED is right of the white LED), but not the precise angular relationship. These experiments provide new insight into spatial memory processes in the cockroach

Follicle-innervating Aδ-low threshold mechanoreceptive neurons form receptive fields through homotypic competition

Abstract The mammalian somatosensory system is comprised of multiple neuronal populations that form specialized, highly organized sensory endings in the skin. The organization of somatosensory endings is essential to their functions, yet the mechanisms which regulate this organization remain unclear. Using a combination of genetic and molecular labeling approaches, we examined the development of mouse hair follicle-innervating low-threshold mechanoreceptors (LTMRs) and explored competition for innervation targets as a mechanism involved in the patterning of their receptive fields. We show that follicle innervating neurons are present in the skin at birth and that LTMR receptive fields gradually add follicle-innervating endings during the first two postnatal weeks. Using a constitutive Bax knockout to increase the number of neurons in adult animals, we show that two LTMR subtypes have differential responses to an increase in neuronal population size: Aδ-LTMR neurons shrink their receptive fields to accommodate the increased number of neurons innervating the skin, while C-LTMR neurons do not. Our findings suggest that competition for hair follicles to innervate plays a role in the patterning and organization of follicle-innervating LTMR neurons