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.

Public Health Relevance

Brain imaging and animal studies have linked disrupted MET receptor tyrosine kinase signaling with autism spectrum disorders (ASD). Rett Syndrome (RTT) is another developmental brain disorder associated with seizures, intellectual disability, sensory-motor and autonomic dysfunction, and non-functional stereotyped hand movements. RTT results from X chromosome linked genetic mutations leading to loss or abnormal function of MeCP2, which is essential for neuronal maturation and synaptic communication involving glutamatergic and inhibitory neurotransmitters, possibly by regulating MET expression. Genetic manipulations of Mecp2 or Met in mice allow us to investigate cellular and molecular mechanisms underlying deficits in wiring of the brain circuits. In this proposal our focus is on the somatosensory thalamocortical system in the broad context of conspicuous somatosensory behavioral phenotypes observed in ASD and RTT. While with a translational flavor, our aim is to uncover biological mechanisms of altered somatosensory thalamocortical information following disrupted gene function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS092216-05S1
Application #
9839804
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mamounas, Laura
Project Start
2015-09-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Lo, Fu-Sun; Erzurumlu, Reha S (2018) Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism. Mol Autism 9:13
Iwasato, Takuji; Erzurumlu, Reha S (2018) Development of tactile sensory circuits in the CNS. Curr Opin Neurobiol 53:66-75
Tang, Qinggong; Lin, Jonathan; Tsytsarev, Vassiliy et al. (2017) Review of mesoscopic optical tomography for depth-resolved imaging of hemodynamic changes and neural activities. Neurophotonics 4:011009
Nag, Okhil K; Stewart, Michael H; Deschamps, Jeffrey R et al. (2017) Quantum Dot-Peptide-Fullerene Bioconjugates for Visualization of in Vitro and in Vivo Cellular Membrane Potential. ACS Nano 11:5598-5613
Lee, Li-Jen; Tsytsarev, Vassiliy; Erzurumlu, Reha S (2017) Structural and functional differences in the barrel cortex of Mecp2 null mice. J Comp Neurol 525:3951-3961
Lo, Fu-Sun; Blue, Mary E; Erzurumlu, Reha S (2016) Enhancement of postsynaptic GABAA and extrasynaptic NMDA receptor-mediated responses in the barrel cortex of Mecp2-null mice. J Neurophysiol 115:1298-306
Lo, Fu-Sun; Erzurumlu, Reha S; Powell, Elizabeth M (2016) Insulin-Independent GABAA Receptor-Mediated Response in the Barrel Cortex of Mice with Impaired Met Activity. J Neurosci 36:3691-7
Suzuki, A; Lee, L-J; Hayashi, Y et al. (2015) Thalamic adenylyl cyclase 1 is required for barrel formation in the somatosensory cortex. Neuroscience 290:518-29
Lo, Fu-Sun; Akkentli, Fatih; Tsytsarev, Vassiliy et al. (2013) Functional significance of cortical NMDA receptors in somatosensory information processing. J Neurophysiol 110:2627-36
Gaspar, Patricia; Erzurumlu, Reha (2013) The birth of the barrels. Dev Cell 27:3-4

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