Hyper-emotional neurophysiology in a rat model of autism

Autism is a pervasive neurodevelopmental disorder of unknown etiology, characterized by a spectrum of symptoms of social impairment, abnormal communication, and unusual restricted, inflexible behaviors. Patients also frequently present various levels of sensory, learning, memory and attention abnormalities, anxiety and phobias, in addition to disturbances in gastrointestinal, sleep, metabolic and immune functions, also with higher rates of physical malformations and seizures. There is currently no empirically based consensus on the causes of symptoms and their remarkable heterogeneity. It is also unknown if associated symptoms are directly linked to autism etiology or if they represent parallel comorbidities. In consequence of our incomplete understanding of the disease process, treatment options are vast and not equally efficacious across all diagnosed individuals. Thus, autism today leads to a lifelong disability that requires significant assistance from health care providers, educational systems and family members. Ultimately, improved diagnostic indicators and personalized therapies should allow the autistic individual to live with reduced costs and more independently. Prenatal exposure to compounds such as valproic acid (VPA) has been associated with higher risk for development of autistic features. The teratogenic and neurodevelopmental effects of VPA in humans are replicated in rodents exposed early in embryonic development, at the time neural tube closure. Thus, the VPA-rat has emerged as a well validated model of autism for controlled investigations of the neurobiological basis of autistic-like symptoms and individual response to environmental interventions. Our laboratory previously demonstrated in the model that the primary sensory cortical, frontal cortical, and amygdala microcircuits are hyper-functional in the pup, in parallel to excessive conditioned fear responses, over-generalization of fear to non-conditioned stimuli, and resistance to fear extinction, in the adult. Together with the full range of autistic symptoms and increasing evidence for local hyper-functional connections and cortical minicolumnpathy in patients, data from the VPA model inspired the hypothesis of autism as an Intense World Syndrome. The theory proposes that the polygenetic background of each individual sets the threshold for susceptibility to their prenatal and post natal environments. At the event of a biological insult, be it exogenous such as VPA-exposure, or genetic, such as a rare set of polymorphisms, a cascade of molecular events would lead to hyper-plastic and hyper-reactive neural microcircuits creating a hyper-functional endophenotype. Depending on the developmental trajectory of each individual, this would lead to abnormalities in four dimensions: hyper-attention, hyper-memory and hyper-perception, and hyper-emotionality. Different patterns of hyper-functional outcomes in each individual would then create a fragmented, intense and even aversive e