RT Journal Article SR Electronic T1 GABAergic cell loss in mice lacking autism-associated gene Sema6A JF bioRxiv FD Cold Spring Harbor Laboratory SP 663419 DO 10.1101/663419 A1 Karlie Menzel A1 Gábor Szabó A1 Yuchio Yanagawa A1 Turhan Cocksaygan A1 Céline Plachez YR 2019 UL http://biorxiv.org/content/early/2019/06/07/663419.abstract AB Background During brain development, a multitude of neuronal networks form as neurons find their correct position within the brain and send out axons to synapse onto specific targets. Altered neuronal connectivity within these complex networks has been reported in Autism Spectrum Disorder (ASD), leading to alterations in brain function and multisensory integration. Semaphorins (also referred to as Semas), a large protein family of about 30 members, have been shown to play an important role in neuronal circuit formation and have been implicated in the etiology of ASD. The purpose of the current study is to investigate how Sema6A mutation affects neuronal connectivity in ASD. Since Sema6A is involved in cell migration, we hypothesized that during brain development the migration of GABAergic interneurons is affected by the loss of Sema6A gene, leading to alterations in Excitatory/Inhibitory (E/I) balance.Methods Sema6A transgenic mice were crossed with either GAD65-GFP mice or GAD67-GFP mice to allow for both a reliable and robust staining of the GABAergic interneuron population within the Sema6A mouse line. Using histological techniques we studies the expression of interneurons subtypes in the Sema6A mutant mice.Results Analysis of Sema6A mutant mice crossed with either GAD65-GFP or GAD67-GFP knock-in mice revealed a reduced number of GABAergic interneurons in the primary somatosensory cortex, hippocampus, and reticular thalamic nucleus (RTN) in adult Sema6A mutant mice. This reduction in cell number appeared to be targeted to the Parvalbumin (PV) interneuron cell population since neither the Calretinin nor the Calbindin expressing interneurons were affected by the Sema6A mutation.Limitations Although the use of animal models has been crucial for understanding the biological basis of autism, the complexity of the human brain can never truly be replicated by these models.Conclusions Taken together, these findings suggest that Sema6A gene loss affects only the fast spiking-PV population and reveal the importance of an axon guidance molecule in the formation of GABAergic neuronal networks and provide insight into the molecular pathways that may lead to altered neuronal connectivity and E/I imbalance in ASD.ASDautism spectrum disordercaBCalbindincaRCalretininCGEcaudal ganglionic eminenceE/Iexcitation/inhibitionGADGlutamate decarboxylaseGFPGreen fibrillary proteinLGElateral ganglionic eminenceMGEmedial ganglionic eminenceMRImagnetic resonance imagingPVParvalbuimRTNreticular thalamic nucleusSema6Asemaphoring 6A