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

Zhu Li,Evelyne Gozal,Gregory Barnes,Rekha Jagadapillai

doi:10.1007/s12035-018-1450-9

Zhu Li, Evelyne Gozal + Show 2 more

Open Access

https://doi.org/10.1007/s12035-018-1450-9

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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.

Highlights

Autism spectrum disorder (ASD) is a neurobiologic disorder with deficits in social skills and language and the presence of restrictive interest/repetitive behaviors [1]
Binding of semaphorin 3F (Sema 3F)-AP is present in all neurite layers of the murine hippocampus but especially high density in CA3 stratum lucidum and inner molecular layer of the dentate gyrus (Fig. 1)
Expression of the Sema 3F protein is detected in these same hippocampal regions but is again decreased by deletion of the Sema 3F gene from either interneurons or pyramidal cells (Fig. 1)

Summary

Introduction

Autism spectrum disorder (ASD) is a neurobiologic disorder with deficits in social skills and language and the presence of restrictive interest/repetitive behaviors [1]. In addition to the 500–1000 genes identified as risk for ASD, multiple environmental causes including maternal stress, diabetes, infection/inflammation, obesity, and medications have been implicated [6]. Additive factors such as terbutaline and maternal stress during gestation produce autistic-like behaviors, spontaneous recurrent convulsive seizures, epileptiform EEGs, and hippocampal gliosis in rodents similar to patients with autism and epilepsy [7]. Those gene– environment interactions may target cortical interneurons, predisposing to autism and epilepsy [8]. The interactions of pregnancy factors with developing brain can impact biological processes such as GABAergic neurogenesis, thereby contributing to the development of ASD

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