Modeling 5-HT-absorbing neurons in neuropathology of autism

DESCRIPTION (provided by applicant): Autism is a postnatal neurodevelopmental disorder diagnosed based on a core of deficits in communication, social interaction, and stereotypic patterns of behavior. Postmortem studies revealed alterations in anatomical organizations and axonal and dendritic arborization in the prefrontal cortex, amygdala and hippocampus, leading to the notion that autism is a disease of synaptic connectivity and that disruption of critical neuronal circuitry underscores the behavioral and cognitive deficits. Family based association studies indicated a link between reduced expression/function of serotonin reuptake transporter (SERT) gene SLC6A4 and autism. Consistent with the idea that reduced SERT function perturbs neuronal circuitry underlying autism, SERT knockout mice exhibit deficits in somatosensory maps, alterations in pyramidal cell dendritic morphology in the infralimbic area and amygdala and enhanced anxiety traits. However, Selective Serotonin Reuptake Transporter Inhibitors (SSRIs) are found to be useful for improving repetitive and compulsive behavior of autistic patients, posting a paradox. Overcoming this paradox will help our understanding the mechanisms underlying the neuropathophysiology of autism and designing rational treatments. To understand the role of SERT deficiency in neuropathophysiology of autism, it is critical to elucidate at which developmental stage do the primary brain lesions occur and what are the mechanisms. The goal of this proposal is to investigate how a transient expression of SERT in a particular set of neurons -- 5-HT-absorbing neurons, during the neonatal stage regulates neuronal synaptic patterning in particular brain regions and whether ablating this SERT function would lead to behavioral deficits seen in autism, by making use of our unique conditional SERT knockout mouse. This proposal is inspired by our recent discovery that 5-HT-absorbing neurons, which absorb extra-synaptic 5-HT via SERT but do not synthesize 5-HT, control stress behavior in C. elegans. We demonstrated that transgenic expression of SERT in the 5-HT-absorbing neurons is necessary and sufficient to correct exaggerated behavior of SERT-null worms. Remarkably, 5-HT-absorbing neurons are present transiently in the neonatal rodent and human brains. In mouse, 5-HT-absorbing neurons are present in primary sensory areas including somatosensory, visual and auditory cortices, the hippocampus, and forebrain sites including the infralimbic area. The proposed experiments will determine the effects of 5-HT-absorbing neuron- specific inactivation of SERT on somatosensory map patterning, axonal and dendritic arborization in the frontal cortex and amygdala, and stress and social behavior. We will assess whether ablating this transient SERT function would lead to lasting alterations in brain anatomy and behavior, and if those effects are sex biased. The results will provide new insights into fundamental mechanisms of 5-HT neurotransmission and illuminate how SERT acts in right cells at right time to regulate brain anatomy and behavioral circuits implicated in autism. PUBLIC HEALTH RELEVANCE: Family based association studies indicated a link between reduced expression/function of serotonin reuptake transporter (SERT) gene SLC6A4 and autism. Consistent with the idea that reduced SERT function perturbs neuronal circuitry underlying autism, SERT knockout mice exhibit deficits in somatosensory maps, alterations in pyramidal cell dendritic morphology in the infralimbic area and amygdala, and enhanced anxiety traits. However, Selective Serotonin Reuptake Transporter Inhibitors (SSRIs) are found to be useful for improving repetitive and compulsive behavior of autistic patients, posting a paradox. To goal of this proposal is to elucidate how SERT acts in right cells at right time to regulate bran anatomy and behavior. By making use of our unique conditional SERT knockout mouse, the proposed experiments will determine the function of a transient SERT expression in specific cells in particular brain regions during the postnatal development. The results will shed light on the mechanisms underlying the neuropathophysiology of autism and provide novel experimental paradigms for designing rational treatments.