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Autism spectrum disorder (ASD) is a complex heterogeneous consortium of pervasive development disorders (PDD) which ranges from atypical autism, autism, and Asperger syndrome affecting brain in the developmental stage. This debilitating neurodevelopmental disorder results in both core as well as associated symptoms. Core symptoms observed in autistic patients are lack of social interaction, pervasive, stereotyped, and restricted behavior while the associated symptoms include irritability, anxiety, aggression, and several comorbid disorders.ASD is a polygenic disorder and is multifactorial in origin. Copy number variations (CNVs) of several genes that regulate the synaptogenesis and signaling pathways are one of the major factors responsible for the pathogenesis of autism. The complex integration of various CNVs cause mutations in the genes which code for molecules involved in cell adhesion, voltage-gated ion-channels, scaffolding proteins as well as signaling pathways (PTEN and mTOR pathways). These mutated genes are responsible for affecting synaptic transmission by causing plasticity dysfunction responsible, in turn, for the expression of ASD.Epigenetic modifications affecting DNA transcription and various pre-natal and post-natal exposure to a variety of environmental factors are also precipitating factors for the occurrence of ASD. All of these together cause dysregulation of glutamatergic signaling as well as imbalance in excitatory: inhibitory pathways resulting in glial cell activation and release of inflammatory mediators responsible for the aberrant social behavior which is observed in autistic patients.In this chapter we review and provide insight into the intricate integration of various genetic, epigenetic, and environmental factors which play a major role in the pathogenesis of this disorder and the mechanistic approach behind this integration.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with symptoms ranging from lack of social interaction and communication deficits to rigid, repetitive, and stereotypic behavior. It has also been associated with comorbidities such as anxiety, aggression, epilepsy, deficit in sensory processing, as well as ADHD (attention deficit hyperactivity disorder). Apart from several behavioral and cognitive complications arising as a result of central nervous system dysfunction, there are various physiological comorbidities such as immune system deregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and gastrointestinal complications which can worsen existing behavioral complications. There are no available treatments for these physiological comorbidities. The prevalence of gastrointestinal complications in ASD ranges from 9% to 70% and it correlates with behaviors consistent with the autistic endophenotype indicating that these are one of the major comorbidities associated with ASD. A strong connection of gut-brain cross talk occurs as a result of gut dysbiosis responsible for excessive production of short-chain fatty acids such as propanoic acid (PPA) by abnormal gut flora in ASD patients. This worsens behavioral, neurochemical, and mitochondrial dysfunction occurring in ASD. These physiological comorbidities are responsible for the generation of free radical species that cause immune system dysfunction leading to synthesis of various pro-inflammatory cytokines and chemokines. This in turn causes activation of microglia. Dietary phytochemicals are thought to be safer and useful as an alternative neurotherapeutic moiety. These compounds provide neuroprotection by modulating signaling pathways such as Nrf2, NF-κB, MAPK pathway or Sirtuin-FoxO pathway. There has been recent evidence in scientific literature regarding the modulation of gut-brain cross talk responsible for behavioral, biochemical, and mitochondrial dysfunction as well as cellular and behavioral sensory alterations by dietary phytochemicals such as curcumin, resveratrol, naringenin, and sulforaphane. These dietary phytochemicals can be formulated in novel brain-targeted delivery systems which overcome their limitation of low oral bioavailability and short half-life leading to prolonged action. Till date, not much work has been done on the development of brain-targeted neurotherapeutics for ASD. In this chapter we discuss plausible mechanisms and evidence from our own and other scientific research for the utilization of curcumin, resveratrol, naringenin, and sulforaphane as neurotherapeutics for ASD.