Increased Serotonin Levels and Unchanged Glutamate and GABA Levels in Thalamic Microdialysates Despite Reduced Cell Numbers in a Valproic Acid-Induced Autism Model

Abstract

Autism spectrum disorders (ASDs) are increasingly prevalent neurodevelopmental disorders characterized by deficits in social skills, abnormal sensory responses and a loss of neuronal cells. A key factor in these differences is thought to be an imbalance between excitation and inhibition. The aim of this study was to measure the levels of γ-aminobutyric acid (GABA), glutamate (GLU) and serotonin (5-HT) in the thalamus of a rat valproic acid (VPA)-induced ASD model and to correlate these levels with the number of thalamic cells. Ten pregnant Wistar rats were injected with 600 mg/kg VPA on Day 12.5 of gestation, whereas five control rats received saline. After the behavioral tests, the male pups were divided into ASD and control groups with ten animals each. At 55 days of age, pups underwent microdialysis under anesthesia, and thalamic samples were analyzed for GABA, GLU and 5-HT levels by ultrahigh-performance liquid chromatography (UHPLC). After microdialysis, the brain sections were stained, and the volumes of the thalamus and hemispheres were calculated using the Cavalieri method, with the number of neurons and glia determined using the optical fractionator method. Compared with the control group, the ASD group presented increased 5-HT levels, an increased hemispheric volume, a decreased thalamic volume and decreased numbers of thalamic neurons and glia. A negative correlation was observed between the GLU content and glial number in the control group but not in the ASD group. These results indicate a disturbed thalamic neurotransmitter balance. We suggest that the increased thalamic 5-HT levels in ASD rats indicates that 5-HT reuptake is inhibited by the GLU content, which remains unchanged, despite the reduced cell number.

Keywords: Autism; GABA; Glia numbers; Glutamate; Microdialysis; Neuron numbers; Serotonin; Thalamus; Valproic acid.