Abstract
Individuals with 22q11.2 microdeletion syndrome (22q11.2 DS) show cognitive and behavioral dysfunctions, developmental delays in childhood and risk of developing schizophrenia and autism. Despite extensive previous studies in adult animal models, a possible embryonic root of this syndrome has not been determined. Here, in neurons from a 22q11.2 DS mouse model (Lgdel+/−), we found embryonic-premature alterations in the neuronal chloride cotransporters indicated by dysregulated NKCC1 and KCC2 protein expression levels. We demonstrate with large-scale spiking activity recordings a concurrent deregulation of the spontaneous network activity and homeostatic network plasticity. Additionally, Lgdel+/− networks at early development show abnormal neuritogenesis and void of synchronized spontaneous activity. Furthermore, parallel experiments on Dgcr8+/− mouse cultures reveal a significant, yet not exclusive contribution of the dgcr8 gene to our phenotypes of Lgdel+/− networks. Finally, we show that application of bumetanide, an inhibitor of NKCC1, significantly decreases the hyper-excitable action of GABAA receptor signaling and restores network homeostatic plasticity in Lgdel+/− networks. Overall, by exploiting an on-a-chip 22q11.2 DS model, our results suggest a delayed GABA-switch in Lgdel+/− neurons, which may contribute to a delayed embryonic development. Prospectively, acting on the GABA-polarity switch offers a potential target for 22q11.2 DS therapeutic intervention.
Highlights
The 22q11.2 deletion syndrome (22q11.2 DS), known as DiGeorge Syndrome (DGS), confers the most significant genetic risk for developing schizophrenia (25–30%) in early adulthood[1], autism spectrum disorders (20–25%)[2] and predisposition to different psychiatric disorders including cognitive, learning, and behavioral impairments (>60%)[3,4]
A wealth of data has demonstrated that the distribution and function of gamma-aminobutyric acid (GABA)-ergic-interneurons are perturbed in the brains of adult 22q11.2 DS patients[7] and that impaired GABAergic-signaling is involved in several neurodevelopmental disorders such as fragile×8, autism[9], schizophrenia[10], Rett Syndrome[9], and Down Syndrome[11]
At 16 DIVs, NKCC1 significantly decreased in Lgdel+/− (112.5 ± 1.1%) compared to its expression at 8 DIVs, but it remained significantly higher than WT (88.4 ± 2.86%; p < 0.05, analysis of variance (ANOVA)) and slightly higher than Dgcr8+/− (102.3 ± 4.64%)
Summary
The 22q11.2 deletion syndrome (22q11.2 DS), known as DiGeorge Syndrome (DGS), confers the most significant genetic risk for developing schizophrenia (25–30%) in early adulthood[1], autism spectrum disorders (20–25%)[2] and predisposition to different psychiatric disorders including cognitive, learning, and behavioral impairments (>60%)[3,4]. The fraction of GABAergic-neurons in rats is already established during the embryonic period from E10.5 through E18.5 and several days after birth[24], and the activity oscillation of these interneurons sets the melody for the early network activity[25] This evidence suggests that altered GABA-ergic signaling might be a key factor in the pathophysiology of neural deficits observed in 22q11.2 DS. Mouse models carrying single-gene mutations were generated, including a heterozygous mouse model for the Dgcr8+/−28, which carries a deletion in the DGS chromosomal region 8 (dgcr8) gene, one of the deleted genes of the 22q11.2 microdeletion This gene is a key component of the Microprocessor complex required for biogenesis of microRNA (miRNA)[29] and holds a fundamental role in the molecular control of brain development[30]. Effects of the dgcr[8] gene deletion were directly associated with the pathophysiology and cognitive phenotypes of the 22q11.2 DS26,31
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
