A Role for Vasoactive Intestinal Peptide Interneurons in Neurodevelopmental Disorders

Abstract

GABAergic inhibitory interneurons of the cerebral cortex expressing vasoactive intestinal peptide (VIP-INs) are rapidly emerging as important regulators of network dynamics and normal circuit development. Several recent studies have also identified VIP-IN dysfunction in models of genetically determined neurodevelopmental disorders (NDDs). In this article, we review the known circuit functions of VIP-INs and how they may relate to accumulating evidence implicating VIP-INs in the mechanisms of prominent NDDs. We highlight recurring VIP-IN-mediated circuit motifs that are shared across cerebral cortical areas and how VIP-IN activity can shape sensory input, development, and behavior. Ultimately, we extract a set of themes that inform our understanding of how VIP-INs influence pathogenesis of NDDs. Using publicly available single-cell RNA sequencing data from the Allen Institute, we also identify several underexplored disease-associated genes that are highly expressed in VIP-INs. We survey these genes and their shared related disease phenotypes that may broadly implicate VIP-INs in autism spectrum disorder and intellectual disability rather than epileptic encephalopathy. Finally, we conclude with a discussion of the relevance of cell type-specific investigations and therapeutics in the age of genomic diagnosis and targeted therapeutics.

Keywords: Autism; Epilepsy; Interneurons; Vasoactive intestinal peptide.

Fig. 1.. Circuit Functions of VIP-INs in NDDs.

Diagrammatic representation of VIP-IN regulated circuits and their impact on biology and disease. VIP-INs are components of several repetitive circuit motifs in the cerebral cortex, including a prominent disinhibitory circuit that is conserved across many brain areas. The activity of VIP-INs not only influences network dynamics, but also the development of normal neural circuits. This shapes behaviours in several important ways, including learning, memory, and attention. Finally, impaired VIP-IN function caused by mutations in certain disease genes may cause abnormal circuit function and behaviour that underlies NDD endophenotypes like autism spectrum disorder (ASD), intellectual disability (ID), and developmental delay (DD). Figure created with BioRender.com.

Fig. 2.. Relative expression of NDD related disease genes in VIP-INs

A) Heatmap showing the expression of genes in a standard NextGen sequencing panel for ASD calculated as a z-score of the trimmed mean LOG2(CPM) across the 5 indicated cell types. “Other IN” includes all INs not in the three main subclasses (VIP, SST, and PV). Genes are sorted based on relative expression in VIP-INs. Below, tan bars on a black background represent expression of each gene as significantly higher in VIP-INs compared to either all Glutamatergic cells (*) or all other INs (†, including PV, SST, and other IN). See Table 1 for raw expression values and statistical test information. B) As in Fig. 2A, but for genes only found on the CHOP Epilepsy v1.0 Panel. C) The same as Fig. 2A–B, but showing genes shared between the two panels. For clarity in Fig. 2A–C, genes with no expression in VIP-INs are omitted, including >20 genes with a mean value of 0 in all cell types, and only the first 50 out of 93 genes from the ASD panel are shown. D) A scatter plot of the trimmed mean LOG2(CPM) expression of all 241 genes, where VIP-IN expression is on the Y axis and is plotted against the other indicated cell types on the X axis. Note that equal expression in VIP-INs compared to another subclass would cause the given data point to fall on the indicated diagonal line. Most genes, particularly those that are low expressing, are expressed higher in all other cell types than in VIP-INs. The sparse distribution of points on the top-left of the diagonal line show genes that are enriched in VIP-INs.

Fig. 3.. Separation of IN subclasses based on NDD diagnostic panel genes

A) TSNE plot generated from the first 50 principal components of the 241 unique genes between the ASD and epilepsy panel using the default settings in MATLAB 2019b. Individual cells are coloured based on the cell subclasses identified by the Allen Brain Institute, indicated in the legend. B) The same done for a random selection of 250 genes. The subtypes are more separable when the ASD/Epilepsy panel gene data is used. C) Receiver operating characteristic (ROC) curves demonstrating the effectiveness of a binary decision tree classifier fitted to the TSNE1 and TSNE2 dimensions in A and B at recovering the original subclasses labelled by the Allen Institute. Each ROC curve is created using the posterior probabilities from the trained decision tree classifier model. For each subclass, the coloured line represents a model based on the ASD/Epilepsy gene panels, and the grey lines represent 5 different selections of 250 random genes. The ‘X’ marks the optimal ROC point for each model. In all cases, the ASD/Panel genes outperform random selections.