Volume 27 Issue 7 - October 10, 2014 PDF
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5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model
Chao-Chuan Wang1, Hui-Ching Lin2, Yun-Han Chan3, Po-Wu Gean3, Yen-Kung Yang4-6, Po-See Chen4-6,*
1 Department of Anatomy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
2 Department and Institute of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
3 Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
4 Department of Psychiatry, College of Medicine, National Cheng Kung University, Tainan, Taiwan
5 Department of Psychiatry, National Cheng Kung University Hospital, Tainan, Taiwan
6 Addiction Research Center, National Cheng Kung University, Tainan, Taiwan
 
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Since the first clearly definition of autism by Dr Leo Kanner in 1943, the etiology of autism has been mystifying scientists for more than a half century. Recently, autism is considered a group of neurodevelopmental disorder with early childhood onset, collectively called autism spectrum disorder (ASD). The amygdala is an important structure contributing to social-emotional behavior. However, the role of the amygdala in ASD remains inconclusive. In our previous studied, we used the valproate (VPA)-induced rat models of ASD to observe the autistic phenotypes and evaluate their synaptic characteristics in the lateral nucleus (LA) of the amygdala. The VPA-exposed offspring demonstrated less social interaction, increased anxiety, enhanced fear learning and impaired fear memory extinction. In vitro electrophysiological recordings of the amygdala showed facilitated excitatory synaptic transmission through a presynaptic mechanism in LA pyramidal neurons. These results suggest that disruption of the synaptic excitatory/inhibitory (E/I) balance in the LA of VPA-exposed rats probably played certain roles in the development of behaviors which are relevant to ASD. In this study, we examined whether disrupted amygdala serotonin homeostasis is linked to ASD. We first discovered that the distribution of tryptophan hydroxylase (TH) immunoreactivity in the caudal raphe system was modulated on postnatal day (PD) 28 of the VPA-exposed offspring. Then, we found a significantly higher serotonin transporter availability in the amygdala of the VPA-exposed offspring on PD 56 by using single photon emission computed tomography and computed tomography co-registration following injection of(123)I-labeled 2-((2-(dimethylamino)methyl)phenyl)thio)-5-iodophenylamine-((123)I[ADAM]). Furthermore, the treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, increased social interaction and improved fear memory extinction in the VPA-exposed offspring. This treatment also reversed the characteristics of miniature excitatory post-synaptic currents as well as paired pulse facilitation observed in lateral amygdala slices. Our results provided further evidence to support the role of the amygdala in characteristic behavioral changes in the rat ASD model. The serotonergic projections which modulate the amygdala function might shed light on the development and treatment of behavioral symptoms exhibited in individuals with ASD.

References:

  1. Aylward, EH, Minshew, NJ, Goldstein, G, Honeycutt, NA, Augustine, AM,Yates, KO, Barta, PE, Pearlson, GD (1999) MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults. Neurology 53:2145–2150.
  2. Azmitia, EC, Singh, JS, Whitaker-Azmitia, PM (2011) Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors. Neuropharmacology 60:1347–1354.
  3. Lin, HC, Gean, PW, Wang, CC, Chan, YH, Chen, PS (2013) The amygdala excitatory/inhibitory balance in a valproate-induced rat autism model. PLoS ONE 8:e55248.
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