Pathophysiological Studies of Monoaminergic Neurotransmission Systems in Valproic Acid-Induced Model of Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. The core syndromes of ASD are deficits in social communication and self-restricted interests and repetitive behaviors. Social communication relies on the proper integration of sensory and motor functions, which is tightly interwoven with the limbic function of reward, motivation, and emotion in the brain. Monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine, are key players in the modulation of neuronal activity. Owing to their broad distribution, the monoamine neurotransmitter systems are well suited to modulate social communication by coordinating sensory, motor, and limbic systems in different brain regions. The complex and diverse functions of monoamine neurotransmission thus render themselves as primary targets of pathophysiological investigation of the etiology of ASD. Clinical studies have reported that children with maternal exposure to valproic acid (VPA) have an increased risk of developing ASD. Extensive animal studies have confirmed that maternal treatments of VPA include ASD-like phenotypes, including impaired social communication and repetitive behavior. Here, given that ASD is a neurodevelopmental disorder, we begin with an overview of the neural development of monoaminergic systems with their neurochemical properties in the brain. We then review and discuss the evidence of human clinical and animal model studies of ASD with a focus on the VPA-induced pathophysiology of monoamine neurotransmitter systems. We also review the potential interactions of microbiota and monoamine neurotransmitter systems in ASD pathophysiology. Widespread and complex changes in monoamine neurotransmitters are detected in the brains of human patients with ASD and validated in animal models. ASD animal models are not only essential to the characterization of pathogenic mechanisms, but also provide a preclinical platform for developing therapeutic approaches to ASD.

Optogenetic Early Life Pain leads to cortical hyperexcitability, nociceptive hypersensitivity and repetitive behavior

“…This notion is supported by the observed high spontaneous cortical ring activity that outlasted sensory stimulation, and is reminiscent of cortical hyperactivity after nerve injury 80 , neuroin ammation 81 or traumatic injury 82,83 . Different from early life stress models imposed by intermittent maternal deprivation 66, 84-86 , perinatal immune activation 87, 88 or perinatal valproic acid treatment 57,89,90 our mice did not show behavior of any major psychopathology such as autism like social de cits, depression or anxiety like behavior or features of schizophrenia or cognitive impairment. Indeed, Avil-ChR2 mice behaved astonishingly equal to controls in all standard Maze tests.…”

Repetitive and compulsive behavior after Early-Life-Pain in mice

“…This notion is supported by the observed high spontaneous cortical ring activity that outlasted sensory stimulation, and is reminiscent of cortical hyperactivity after nerve injury [92], neuroin ammation [93] or traumatic injury [94,95]. Different from early life stress models imposed by intermittent maternal deprivation [74,[96][97][98], perinatal immune activation [99,100] or perinatal valproic acid treatment [71,101,102] our mice did not show behavior of autism like social de cits, depression or anxiety or features of schizophrenia or cognitive impairment. Indeed, Avil-ChR2 mice behaved astonishingly equal to controls in all standard maze tests.…”

The influence of continuous prenatal exposure to valproic acid on physical, nociceptive, emotional and psychomotor responses during adolescence in mice: Dose-related effects within sexes

“…It is for this reason that the results of the present study are not extensively discussed using neurobehavioral findings of the VPA rodent model of ASD ( Schneider and Przewłocki, 2005 ; Snow et al, 2008 ; Martin and Manzoni, 2014 ). Also, VPA-induced impairment of inhibitory and excitatory neurotransmission takes place in different brain regions, including the cortex, striatum, hippocampus, amygdala, and cerebellum ( Biggs et al, 1992 ; Peichev, 1992 ; Löscher, 1993 ; Olexová et al, 2016 ; Puig-Lagunes et al, 2021 ; Kuo and Liu, 2022 ), which may be associated with a poor behavioral outcome. However, in the model of prenatal exposure to VPA, the offspring is indirectly exposed and these neurochemical findings cannot explain the behavioral characteristics.…”

“…The VPA-induced ASD-like animal model has been widely used to examine the neurobiology associated with affected responses to social context and social novelty ( Hughes et al, 2020 ; Kuo and Liu, 2022 ). Findings obtained in the VPA model of ASD revealed communication deficits in VPA-exposed rats during infancy, adolescence and adulthood, with the most pronounced impact on adolescent animals ( Gzielo et al, 2020 ).…”