Probing Disrupted Cortico-thalamic Interactions in Autism Spectrum Disorders

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DESCRIPTION (provided by applicant): Autism Spectrum Disorders (ASD) represents a group of severe, highly heritable, neurobehavioral syndromes with heterogeneous phenotype. The clinical features of autistic children are notable for an unawareness of their surrounding environment, impaired language and social interactions, and repetitive behaviors. They often exhibit relatively normal initial maturation followed by stagnation or regression. The underlying cause of this clinical course is unknown. Here, we propose to test a novel idea-- that disrupted interactions between the thalamus and the cortex during their circuit maturation underlie this developmental sequel. Recently, there has been increasing interest in the idea that ASD might involve dysfunction of experience- dependent circuit maturation and refinement. Sensory systems, such as the visual system, are thought to develop sequentially in a feed forward manner during sensitive periods in early development. However, this model for development has been challenged by our recent findings demonstrating overlap in the timing of refinement of thalamic and cortical critical periods. Our hypothesis is that cortical feedback to the thalamus drives the refinement of thalamic synaptic circuits, and the resulting thalamic function influences cortical development. Disruption of this interaction could result in the late developmental abnormalities observed in ASD. To test this hypothesis, we will take advantage of MeCP2 deficient mouse, an animal model of Rett Syndrome (RTT). RTT is a neurodevelopment disorder associated with ASD. The visual system will be used as an experimental system for understanding the developmental relationship between thalamus and cortex. MeCP2 null mice exhibit impaired development of visual function both at the thalamic and cortical level. In this proposal, we will selectively disrupt the expression of the MeCP2 gene either cortically or in the retino-thalamic circuitry and assess the functional maturation of retinogeniculate or cortical circuits respectively. If our hypothesis is true, selective cortical defect should affect the experience-dependent sensitive period for thalamic circuit plasticity and a focal deficit in the retino-thalamic circuitry will ultimately affect cortical development. Our results would transform the fundamental thinking of the mammalian central nervous system development. A feed forward and feedback interaction between the CNS structures would mean that defects in one area could affect the other and amplify over time. In addition, interaction between the two structures raises the possibility that changes in one structure can compensate for defects in the other. Thus, a deeper understanding of the developmental relationship between the thalamus and cortex could have implications in neurodevelopment disorders such as autism spectrum disorders. PUBLIC HEALTH RELEVANCE: Sensory information (such as vision, hearing and touch) is transmitted through various stations in the brain as it is relayed to the cortex. In this proposal we test a novel hypothesis that during development, the cortex sends information to guide the development of these stations. A feed-forward and feedback communication between different regions of the brain could result in a spreading of an initially focal abnormality. This could be the underlying cause of neurodevelopment diseases such as Rett Syndrome and Autism Spectrum Disorders. Thus it is important to understand the importance of communication between different areas of the brain during development.