GABAergic cell loss in mice lacking autism-associated geneSema6A

Abstract

AbstractBackgroundDuring 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 howSema6Amutation affects neuronal connectivity in ASD. SinceSema6Ais involved in cell migration, we hypothesized that during brain development the migration of GABAergic interneurons is affected by the loss ofSema6Agene, leading to alterations in Excitatory/Inhibitory (E/I) balance.MethodsSema6Atransgenic 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 theSema6Amouse line. Using histological techniques we studies the expression of interneurons subtypes in the Sema6A mutant mice.ResultsAnalysis ofSema6Amutant 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 adultSema6Amutant 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 theSema6Amutation.LimitationsAlthough 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.ConclusionsTaken together, these findings suggest thatSema6Agene 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.