Deletion of Semaphorin 3F in Interneurons Is Associated with Decreased GABAergic Neurons, Autism-like Behavior, and Increased Oxidative Stress Cascades

Abstract

Autism and epilepsy are diseases which have complex genetic inheritance. Genome-wide association and other genetic studies have implicated at least 500+ genes associated with the occurrence of autism spectrum disorders (ASD) including the human semaphorin 3F (Sema 3F) and neuropilin 2 (NRP2) genes. However, the genetic basis of the comorbid occurrence of autism and epilepsy is unknown. The aberrant development of GABAergic circuitry is a possible risk factor in autism and epilepsy. Molecular biological approaches were used to test the hypothesis that cell-specific genetic variation in mouse homologs affects the formation and function of GABAergic circuitry. The empirical analysis with mice homozygous null for one of these genes, Sema 3F, in GABAergic neurons substantiated these predictions. Notably, deletion of Sema 3F in interneurons but not excitatory neurons during early development decreased the number of interneurons/neurites and mRNAs for cell-specific GABAergic markers and increased epileptogenesis and autistic behaviors. Studies of interneuron cell-specific knockout of Sema 3F signaling suggest that deficient Sema 3F signaling may lead to neuroinflammation and oxidative stress. Further studies of mouse KO models of ASD genes such as Sema 3F or NRP2 may be informative to clinical phenotypes contributing to the pathogenesis in autism and epilepsy patients.

GABAergic cell loss in mice lacking autism-associated geneSema6A

“…The differences in cell number reduction between the 2 studies might be explained by the fact that Sema6A and Sema3F play different roles in either the GABAergic cell production, migration or maturation. Sema7A knockout mice also displayed a GABAergic cell loss in the hippocampus, however it was specifically located in the CA1 area [56] whereas our data showed that in Sema6A mutant mice all the hippocampal sub-regions had a reduction in GABAergic cell number. Taken together, our data suggest the importance of Sema6A gene in either the production, proliferation and/or migration of GABAergic interneurons since the disruption of this gene leads to a GABAergic cell loss in several brain areas.…”

“…Indeed failure in GABAergic circuitry formation was described in the Sema7A knockout mice, however the GABAergic cell loss was only reported in layer 4 of the barrel cortex [55] compared to our results showing that all the cortical layers are affected in the Sema6A mutation. More recently, Greg Barnes' group published an informative study on interneuronspecific knockout mouse of Sema3F [56]. Their data showed a 20% reduction of GABAergic cells in the somatosensory cortex while we report a 50% reduction of GAD65-GFP positive cells and 26% reduction of GAD67-GFP positive cells in the same cortical area.…”

“…Such defects in CC formation were also reported in Sema3A knockout mice [33,53] and provide more evidence for a role of semaphorin members in ASD as 1/3 of individuals with autism have an abnormal CC [54]. While most studies have focused on the importance of semaphorins in the control of neuronal migration and axon guidance during brain development, recent studies have reported the role of semaphorins in the maturation of cortical circuits [55,56]. Indeed failure in GABAergic circuitry formation was described in the Sema7A knockout mice, however the GABAergic cell loss was only reported in layer 4 of the barrel cortex [55] compared to our results showing that all the cortical layers are affected in the Sema6A mutation.…”

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

“…Importantly, Sema3F signaling has been also implicated in the pathogenesis of ASD. Sema3F‐ or NRP2‐deficient mice show both behavioral and neuropathological aspects of ASD , and Sema3F interacts with multiple ASD‐related genes, e.g., fragile X mental retardation protein or MECP2 . Thus, by linking Sema3F and CRMP2 signaling and comparing the histological as well as behavioral effects of their deficiency, our data strongly implicate that the Sema3F‐CRMP2 signaling plays an important role in ASD pathogenesis.…”

CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling

“…Importantly, Sema3F signaling has been also implicated in the pathogenesis of ASD. Sema3F or NRP2 deficient mice show both behavioral and neuropathological aspects of ASD (Li et al, 2019) and Sema3F interacts with multiple ASD-related genes e.g. fragile X mental retardation protein or MECP2 (Degano et al, 2009).…”