GABAergic cell loss in mice lacking autism-associated geneSema6A

Abstract

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. BACKGROUND:Leo Kanner was the first to describe early infantile autism in 1944 [1] and since then tremendous effort has been made to not only understand the causes of Autism Spectrum Disorder (ASD) but also to improve early diagnosis. While it appears that the causation of autism is very complex, one can learn from studying abnormalities in brain structure or function. Magnetic Resonance Imaging (MRI) as well as histological techniques using brain tissue from individuals with autism have provided invaluable data in the quest to elucidate brain differences occurring in ASD. Indeed many studies that have examined brain anatomy at a structural and/or cellular level have reported an increased volume for total brain, parieto-temporal lobe, and cerebellar hemispheres in ASD [2]. Brain growth and connectivity differe...

De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy

“…25,26 Furthermore, Sema6A contributes to GABAergic interneuron migration during brain development, and its disruption might be an underlying cause of autism spectrum disorder (ASD). 27 In addition, this pathophysiological mechanism might be shared with epilepsy. 27,28 Consistent with this hypothesis, SEMA6B was expressed in GABAergeic neurons (Figure S6B), and disruption of SEMA6B function in GABAergic neurons might contribute to epilepsy in humans.…”

“…27 In addition, this pathophysiological mechanism might be shared with epilepsy. 27,28 Consistent with this hypothesis, SEMA6B was expressed in GABAergeic neurons (Figure S6B), and disruption of SEMA6B function in GABAergic neurons might contribute to epilepsy in humans. Our zebrafish sema6ba/b-ex.17-injected crispants demonstrated increased PTZ-mediated hyperactive responses compared with the response of the sema6ba/ b-ex.2-injected larvae.…”

Transcriptome Study in Sicilian Patients with Autism Spectrum Disorder

“…This gene, in particular, has been evaluated as being involved in the development of neuronal networks, regulated by intracellular signaling events; furthermore, altered neuronal connectivity is reported in individuals with ASD [99][100][101][102][103]. Menzel et al (2019), through the use of genetically modified mice, observed how the knockout of SEMA6A is relevant for the formation of GABAergic interneurons in several brain areas involved in ASD, such as the primary somatosensory cortical areas, the hippocampus, and the Thalamic Reticular Nucleus (RTN), consequently leading to alterations in excitatory/inhibitory (E/I) balance and neurodevelopmental defects/ASD [99]. Considering that our data show an overexpression of SEMA6A, it is reasonable to think that it may have an important role in the phenotype of subjects with ASD, as proposed by the authors mentioned above.…”