Deep Brain Stimulation Modified Autism-Like Deficits via the Serotonin System in a Valproic Acid-Induced Rat Model.

Han-Fang Wu,Hui-Ching Lin,Po Chen,I-Tuan Chen,Ya-Ting Hsu,Yi-Ju Chen,Ting-Yi Lu,Ming-Chia Chu

doi:10.3390/ijms19092840

Abstract

Deep brain stimulation (DBS) is known to be a promising treatment for resistant depression, which acts via the serotonin (5-hydroxytryptamine, 5-HT) system in the infralimbic prefrontal cortex (ILPFC). Previous study revealed that dysfunction of brain 5-HT homeostasis is related to a valproate (VPA)-induced rat autism spectrum disorder (ASD) model. Whether ILPFC DBS rescues deficits in VPA-induced offspring through the 5-HT system is not known. Using VPA-induced offspring, we therefore explored the effect of DBS in autistic phenotypes and further investigated the underlying mechanism. Using combined behavioral and molecular approaches, we observed that applying DBS and 5-HT1A receptor agonist treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reversed sociability deficits, anxiety and hyperactivity in the VPA-exposed offspring. We then administered the selective 5-HT1A receptor antagonist N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY 100635), following which the effect of DBS in terms of improving autistic behaviors was blocked in the VPA-exposed offspring. Furthermore, we found that both 8-OH-DPAT and DBS treatment rescued autistic behaviors by decreasing the expressions of NR2B subunit of N-methyl-D-aspartate receptors (NMDARs) and the β3 subunit of γ-aminobutyric acid type A receptors (GABAAR) in the PFC region. These results provided the first evidence of characteristic behavioral changes in VPA-induced offspring caused by DBS via the 5-HT system in the ILPFC.

Highlights

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment of social interaction, and repetitive and restricted-interests behaviors [1,2]
We examined whether infralimbic prefrontal cortex (ILPFC) Deep brain stimulation (DBS) and a 5-HT1A receptor agonist reversed the decreased social interaction, increased anxiety and increased locomotion in a VPA-induced ASD model
The results revealed that ILPFC DBS resulted in a dramatic increase in the time spent in chamber S1 and decreased the time spent in chamber E in the VPA-exposed offspring

Summary

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment of social interaction, and repetitive and restricted-interests behaviors [1,2]. ASD is considered to be caused by an imbalance between excitation and inhibition (E/I) in neural circuits, resulting in impairment of social and emotional systems [3]. There is no effective medication to address the core characteristic symptoms of ASD in the clinical setting. Deep brain stimulation (DBS) has been demonstrated to control the motor symptoms of Parkinson’s disease (PD); it has emerged as a therapy for psychiatric diseases, including obsessive-compulsive disorder (OCD), depression, Alzheimer’s disease and drug addiction, in recent years [4,5,6,7,8,9]. Clinical evidence suggests that DBS modulates dysfunctional limbic networks and their effects on neuropsychiatric disorders, including OCD, treatment-resistant depression (TRD), and Tourette’s syndrome [10]. As DBS modulates the E/I balance, it is a potential therapy for ASD

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