ABSTRACT
Accumulating evidence suggests that dysfunction of the amygdala is related to abnormal fear processing, anxiety, and social behaviors noted in autistic spectrum disorders (ASDs). In addition, studies have shown that disrupted brain serotonin homeostasis is linked to ASD. With a valproate (VPA)-induced rat ASD model, we investigated the possible role of amygdala serotonin homeostasis in autistic phenotypes and further explored the underlying mechanism. We first discovered that the distribution of tryptophan hydroxylase 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, 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. 8-OH-DPAT treatment also reversed the characteristics of miniature excitatory post-synaptic currents as well as paired pulse facilitation observed in lateral amygdala slices. These results provided further evidence to support the role of the amygdala in characteristic behavioral changes in the rat ASD model. The serotonergic projections that modulate the amygdala function might play a certain role in the development and treatment of behavioral symptoms exhibited in individuals with ASD.
Subject(s)
8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Amygdala/drug effects , Autistic Disorder/drug therapy , Behavior, Animal/drug effects , Receptor, Serotonin, 5-HT1A/drug effects , Serotonin 5-HT1 Receptor Agonists/pharmacology , Social Behavior , Valproic Acid , Amygdala/diagnostic imaging , Amygdala/metabolism , Amygdala/physiopathology , Animals , Autistic Disorder/chemically induced , Autistic Disorder/diagnosis , Autistic Disorder/metabolism , Autistic Disorder/physiopathology , Autistic Disorder/psychology , Cinanserin/analogs & derivatives , Disease Models, Animal , Excitatory Postsynaptic Potentials , Extinction, Psychological/drug effects , Fear/drug effects , Female , Male , Memory/drug effects , Miniature Postsynaptic Potentials , Multimodal Imaging/methods , Pregnancy , Prenatal Exposure Delayed Effects , Radiopharmaceuticals , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Time Factors , Tomography, Emission-Computed, Single-Photon , Tomography, X-Ray Computed , Tryptophan Hydroxylase/metabolismABSTRACT
The amygdala is an important structure contributing to socio-emotional behavior. However, the role of the amygdala in autism remains inconclusive. In this study, we used the 28-35 days valproate (VPA)-induced rat model of autism to observe the autistic phenotypes and evaluate their synaptic characteristics in the lateral nucleus (LA) of the amygdala. The VPA-treated offspring demonstrated less social interaction, increased anxiety, enhanced fear learning and impaired fear memory extinction. Slice preparation and electrophysiological recordings of the amygdala showed significantly enhanced long-term potentiation (LTP) while stimulating the thalamic-amygdala pathway of the LA. In addition, the pair pulse facilitation (PPF) at 30- and 60-ms intervals decreased significantly. Whole-cell recordings of the LA pyramidal neurons showed an increased miniature excitatory postsynaptic current (EPSC) frequency and amplitude. The relative contributions of the AMPA receptor and NMDA receptor to the EPSCs did not differ significantly between groups. These results suggested that the enhancement of the presynaptic efficiency of excitatory synaptic transmission might be associated with hyperexcitibility and enhanced LTP in LA pyramidal neurons. Disruption of the synaptic excitatory/inhibitory (E/I) balance in the LA of VPA-treated rats might play certain roles in the development of behaviors in the rat that may be relevant to autism. Further experiments to demonstrate the direct link are warranted.