Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Sep 19;19(9):2840.
doi: 10.3390/ijms19092840.

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

Han-Fang Wu  1 , Yi-Ju Chen  2 , Ming-Chia Chu  3 , Ya-Ting Hsu  4 , Ting-Yi Lu  5 , I-Tuan Chen  6 , Po See Chen  7   8 , Hui-Ching Lin  9   10   11
Affiliations

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

Han-Fang Wu et al. Int J Mol Sci. .

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.

Keywords: autism spectrum disorder; deep brain stimulation; serotonin system; valproic acid.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
ILPFC DBS improved social interaction, anxiety and hyperlocomotion in the VPA-exposed offspring. (A) Time spent by the VPA-exposed offspring in chamber E, the center chamber, and chamber S1 during the three-chamber social interaction test following seven days of DBS treatment; (B) preference indices of the saline- and VPA-exposed offspring after DBS treatment; (C) bar chart showing the percentage of time spent in the open arms after DBS treatment; (D) bar chart revealing the total distance traveled in the open field test. * p < 0.05 vs. saline/sham; *** p < 0.001 vs. saline/sham; # p < 0.05 vs. VPA/sham; ## p < 0.01 vs. VPA/sham; ### p < 0.001 vs. VPA/sham. Sample sizes (n): saline/sham n = 7, saline/DBS n = 5, VPA/sham n = 9, VPA/DBS n = 7.
Figure 2
Figure 2
WAY 100635 blocked the improvements in social interaction, anxiety and hyperlocomotion instigated by ILPFCDBS in the VPA-exposed offspring. (A) Duration of latency on entering chamber E, the center chamber, and chamber S1 during the three-chamber social interaction test; (B) preference index in the social interaction test; (C) percentage of time spent in the open arms; (D) total distance traveled in the open field test. * p < 0.05 vs. VPA/sham; *** p < 0.05 vs. VPA/sham; # p < 0.05 vs. VPA/DBS; ## p < 0.01 vs. VPA/DBS; ### p < 0.001 vs. VPA/DBS. Sample sizes (n): saline/sham n = 7, VPA/sham n = 9, VPA/DBS n = 5, VPA/DBS/WAY 100635 n = 5.
Figure 3
Figure 3
8-OH-DPAT treatment increased social interaction and ameliorated anxiety and hyperlocomotion in the VPA-exposed offspring. (A) Time spent by the VPA-exposed offspring in chamber E, the center chamber, and chamber S1 during the three-chamber social interaction test following local infusion of 8-OH-DPAT (10 μg/μL) into the ILPFC; (B) preference index in the social interaction test; (C) the percentage in the open arms after 8-OH-DPAT treatments; (D) bar chart revealing the total distance traveled in the open field test. * p < 0.05 vs. saline/vehicle; ** p < 0.01 vs. saline/vehicle; *** p < 0.001 vs. saline/vehicle; # p < 0.05 vs. VPA/vehicle; ## p < 0.01 vs. VPA/vehicle; ### p < 0.001 vs. VPA/vehicle. Sample sizes (n): saline/vehicle n = 6, saline/8-OH-DPAT n = 7, VPA/vehicle n = 8, VPA/8-OH-DPAT n = 5.
Figure 4
Figure 4
One-day ILPFC DBS combined with 8-OH-DPAT treatment facilitated improvement of social interaction and social preference in the VPA-exposed offspring. (A) Duration of latency on entering chamber E, the center chamber, and chamber S1 during the three-chamber social interaction test; (B) preference index in the social interaction test. *** p < 0.001 vs. saline-; ### p < 0.001 vs. VPA. Sample sizes (n): saline n = 5, VPA n = 8, VPA/DBS 1 day/8-OH-DPAT n = 4, saline/DBS 7 days n = 5.
Figure 5
Figure 5
DBS and 8-OH-DPAT treatment reversed the increased expressions of NMDAR subunit NR2B and the GABAAR β3 subunit in the VPA-exposed offspring. (A) Representative blots and quantification showing the synapse NMDAR subunit NR2B expression after 8-OH-DPAT treatment in the VPA-exposed offspring. Sample sizes (n): Saline n = 12, VPA n = 9, VPA/8-OH-DPAT n = 5; (B) representative blots and quantification showing the synapse GABAAR β3 subunit expression after 8-OH-DPAT treatment in the VPA-exposed offspring. Sample sizes (n): Saline n = 4, VPA n = 4, VPA/8-OH-DPAT n = 4; (C) immunoblots and quantification showing the synapse NMDAR subunit NR2B expression after seven days of DBS and after three days of DBS combined with 8-OH-DPAT treatments in the VPA-exposed offspring. Sample sizes (n): VPA n = 14, VPA/DBS n = 12, VPA/DBS/8-OH-DPAT n = 12; (D) western blotting showing the synapse GABAAR β3 subunit expression after seven days of DBS and after three days of DBS combined with 8-OH-DPAT treatment in the VPA-exposed offspring. Sample sizes (n): VPA n = 8, VPA/DBS n = 6, VPA/DBS/8-OH-DPAT n = 6. * p < 0.05 vs. saline/vehicle; ** p < 0.01 vs. saline/vehicle; * p < 0.05 vs. saline; ** p < 0.01 vs. saline; ** p < 0.01 vs. VPA; *** p < 0.001 vs. VPA; ## p < 0.01 vs. VPA; ### p < 0.001 vs. VPA.
Figure 6
Figure 6
Experimental design of ILPFC DBS applied to the VPA-exposed offspring. (A) Schematic representation flow chart of the experimental design; (B) verification of unilateral DBS electrode placement on the right-hand side by Nissl staining of the ILPFC. Scale bar, 1 mm.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Rapin I., Tuchman R.F. Autism: Definition, neurobiology, screening, diagnosis. Pediatr. Clin. N. Am. 2008;55:1129–1146. doi: 10.1016/j.pcl.2008.07.005. - DOI - PubMed
    1. Ratajczak H.V. Theoretical aspects of autism: Causes—A review. J. Immunotoxicol. 2011;8:68–79. doi: 10.3109/1547691X.2010.545086. - DOI - PubMed
    1. Rubenstein J.L., Merzenich M.M. Model of autism: Increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003;2:255–267. doi: 10.1034/j.1601-183X.2003.00037.x. - DOI - PMC - PubMed
    1. Hamani C., Pilitsis J., Rughani A.I., Rosenow J.M., Patil P.G., Slavin K.S., Abosch A., Eskandar E., Mitchell L.S., Kalkanis S. Deep brain stimulation for obsessive-compulsive disorder: Systematic review and evidence-based guideline sponsored by the american society for stereotactic and functional neurosurgery and the congress of neurological surgeons (CNS) and endorsed by the CNS and american association of neurological surgeons. Neurosurgery. 2014;75:327–333. - PubMed
    1. Holtzheimer P.E., Kelley M.E., Gross R.E., Filkowski M.M., Garlow S.J., Barrocas A., Wint D., Craighead M.C., Kozarsky J., Chismar R., et al. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch. Gen. Psychiatry. 2012;69:150–158. doi: 10.1001/archgenpsychiatry.2011.1456. - DOI - PMC - PubMed

MeSH terms

-