Low-Frequency rTMS Ameliorates Autistic-Like Behaviors in Rats Induced by Neonatal Isolation Through Regulating the Synaptic GABA Transmission.

Tao Tan,Haitao Xu,Zhifang Dong,Yu Tian Wang,Wei Wang,Zhilin Huang

doi:10.3389/fncel.2018.00046

Abstract

Patients with autism spectrum disorder (ASD) display abnormalities in neuronal development, synaptic function and neural circuits. The imbalance of excitatory and inhibitory (E/I) synaptic transmission has been proposed to cause the main behavioral characteristics of ASD. Repetitive transcranial magnetic stimulation (rTMS) can directly or indirectly induce excitability and synaptic plasticity changes in the brain noninvasively. However, whether rTMS can ameliorate autistic-like behaviors in animal model via regulating the balance of E/I synaptic transmission is unknown. By using our recent reported animal model with autistic-like behaviors induced by neonatal isolation (postnatal days 1–9), we found that low-frequency rTMS (LF-rTMS, 1 Hz) treatment for 2 weeks effectively alleviated the acquired autistic-like symptoms, as reflected by an increase in social interaction and decrease in self-grooming, anxiety- and depressive-like behaviors in young adult rats compared to those in untreated animals. Furthermore, the amelioration in autistic-like behavior was accompanied by a restoration of the balance between E/I activity, especially at the level of synaptic transmission and receptors in synaptosomes. These findings indicated that LF-rTMS may alleviate the symptoms of ASD-like behaviors caused by neonatal isolation through regulating the synaptic GABA transmission, suggesting that LF-rTMS may be a potential therapeutic technique to treat ASD.

Highlights

Autism spectrum disorders (ASDs) are neuropsychiatric developmental diseases characterized by social impairment, repetitive stereotyped behaviors and language retardation (Geschwind, 2011)
The maximal magnetic field is under the center of the coil, but the maximal induced electric field is under the windings of the coil
We confirm that newborn rats subjected to neonatal isolation from postnatal day (PND) 1–9 display autistic-like behaviors at the age of young adults and demonstrate that these behavioral alterations are associated with an abnormal increase in inhibitory synaptic transmission and synaptic GABAα1R and vesicular GABA transporter (VGAT)

Summary

Introduction

Autism spectrum disorders (ASDs) are neuropsychiatric developmental diseases characterized by social impairment, repetitive stereotyped behaviors and language retardation (Geschwind, 2011). Frustratingly little is understood about the causal mechanisms underlying this complex disorder, recent studies have suggested that an imbalance of excitatory and inhibitory (E/I) synaptic transmission may cause the main behavioral characteristics of ASD (Gatto and Broadie, 2010). This hypothesis has been validated in ASD patients (Cornew et al, 2012) and different ASD animal models (Lee et al, 2017). Based on ASD animal models, an early illuminating review Rubenstein and Merzenich (2003) suggested that an increased E/I (excitation and inhibition) ratio in sensory, mnemonic, social and emotional systems can cause ASD. The latest review Lee et al (2017) reminded that the pathogenic mechanisms underlying E/I imbalance in ASD are far more complex than might have been expected

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