There is increasing evidence, implicating disruption of excitatory and inhibitory neurotransmission in the etiology of Autism Spectrum Disorders (ASD) and Rett Syndrome (RTT). Specific genetic effects are associated with these developmental disorders. MET receptor and it ligand hepatocyte growth factor (HGF) and both are expressed in the developing brain. The human gene MET, which encodes MET receptor tyrosine kinase has been identified as a prominent risk factor for ASD. RTT is a neurodevelopmental disorder caused by mutations in the MECP2 gene. Met and Mecp2 loss-of-function mouse models provide invaluable opportunities in understanding morphological and physiological changes in various brain regions, and they allow for development of therapeutic strategies. Both ASD and RTT affected children display distinct somatosensory behavioral proclivities suggesting specific defects in somatosensory information processing. We focus on the somatosensory thalamocortical circuit physiology and in vivo functional analyses in development, using region-specific genetic loss of function mouse models to uncover basic scientific mechanisms of thalamocortical circuitry defects following genetic disruption of these two genes associated with ASD and RTT. Our preliminary results in the Bird mouse model of MeCP2 deficiency indicate that the balance of excitation and inhibition in Layer 4 excitatory neurons of barrel cortex is biased toward inhibition. In contrast when Met signaling is disrupted in cortical excitatory neurons, heterozygous mice show loss of inhibition. We focus on the mouse primary somatosensory (whisker 'barrel') cortex because of its patterned organization and well-characterized development and plasticity. We combine mouse genetics with electrophysiological, functional imaging, biochemical, and behavioral analyses to understand the cellular mechanisms and consequences of thalamocortical circuitry defects following these specific genetic disruptions.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
