Our project is centered on studies of the brain that will help us better understand how neural networks that often go haywire in psychiatric disorders are built during development. Normal functioning of the cerebral cortex depends critically on the precise balance of excitatory neurons and inhibitory neurons, which together control the flow of information and synchronization of neural networks necessary for higher order brain activity. Disturbances in forebrain GABAergic inhibitory interneurons can affect the delicate balance between excitation and inhibition, leading to hyperexcitability and neuropsychiatric diseases such as epilepsy, autism, other intellectual disabilities, schizophrenia, and mood disorders. While these conditions are distinct from each other, they typically have in common disturbances in the number/distribution/function of forebrain interneurons. This suggests related mechanisms are in play to establish and maintain the homeostatic balance of excitatory and inhibitory signals necessary for normal brain activity and that disruption of interneuron function leads to imbalances with pathological consequences. Great progress has been made in recent years by the identification genes that contribute to psychiatric disorders in humans, including the highly conserved neuronal EphB2 receptor tyrosine kinase. Knockout mice are particularly attractive animal models to analyze how mutation of such genes in the rodent affects interneuron development and leads to psychiatric-type behaviors. Despite these advancements our knowledge of the molecular mechanisms that regulate interneuron migration and integration into the cortical network remains rudimentary. In our ongoing studies of the EphB receptors and their transmembrane ephrin-B ligands, we have generated new conditional brain-specific mutant mice and find they present with seizures and abnormal hyperexcitable autistic-like behaviors that are associated with defective interneuron populations in the cortex and hippocampus. Our new data allows us to hypothesize that Eph/ephrin-B cell-to-cell signaling is an essential component of interneurons required for normal excitatory/inhibitory (E/I) balance. To further build this new link between Eph/ephrin-B signaling, interneuron development, and E/I balance, we will determine how specific loss of ephrin-B's within the GABAergic cell type affects interneuron migration into the developing forebrain and axonal/dendritic/synaptic morphology in the developed brain. Electrophysiological and behavioral studies will assess how loss of ephrin-B in inhibitory neurons affects E/I balance and leads to abnormal autistic-like behaviors. To complement the analysis of GABAergic specific conditional knockouts, intracellular ephrin-B mutants will be studied to determine the role of reverse signaling in interneurons. Through the described experiments we will gain a better understanding of how the ephrin-B proteins participate in regulating cortical E/I balance and function to prevent formation of abnormal psychiatric-type behaviors.

Public Health Relevance

Although poorly understood at the molecular level, psychiatric disorders like epilepsy, autism, and schizophrenia are typically associated with defects in the inhibitory interneuron circuits that normally function to dampen the brain's excitation signals. The proposed studies are based on our new findings that ephrin-B mutant mice exhibit abnormal autistic-like behaviors and seizures that are associated with defective interneuron populations in the brain. Our experiments will further build on this important and significant new concept that ephrin-B proteins are key players that regulate interneuron development and function, and are needed to prevent formation of abnormal psychiatric-type disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01MH066332-11A1
Application #
8761137
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Panchision, David M
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Robichaux, Michael A; Chenaux, George; Ho, Hsin-Yi Henry et al. (2014) EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding. Proc Natl Acad Sci U S A 111:2188-93
Raft, Steven; Andrade, Leonardo R; Shao, Dongmei et al. (2014) Ephrin-B2 governs morphogenesis of endolymphatic sac and duct epithelia in the mouse inner ear. Dev Biol 390:51-67
Villar-Cervino, Verona; Molano-Mazon, Manuel; Catchpole, Timothy et al. (2013) Contact repulsion controls the dispersion and final distribution of Cajal-Retzius cells. Neuron 77:457-71
Cibert-Goton, Vincent; Yuan, Guanglu; Battaglia, Anna et al. (2013) Involvement of EphB1 receptors signalling in models of inflammatory and neuropathic pain. PLoS One 8:e53673
Srivastava, Nishi; Robichaux, Michael A; Chenaux, George et al. (2013) EphB2 receptor forward signaling controls cortical growth cone collapse via Nck and Pak. Mol Cell Neurosci 52:106-16
Xu, Nan-Jie; Henkemeyer, Mark (2012) Ephrin reverse signaling in axon guidance and synaptogenesis. Semin Cell Dev Biol 23:58-64
Xu, Nan-Jie; Sun, Suya; Gibson, Jay R et al. (2011) A dual shaping mechanism for postsynaptic ephrin-B3 as a receptor that sculpts dendrites and synapses. Nat Neurosci 14:1421-9
Dravis, Christopher; Henkemeyer, Mark (2011) Ephrin-B reverse signaling controls septation events at the embryonic midline through separate tyrosine phosphorylation-independent signaling avenues. Dev Biol 355:138-51
Catchpole, Timothy; Henkemeyer, Mark (2011) EphB2 tyrosine kinase-dependent forward signaling in migration of neuronal progenitors that populate and form a distinct region of the dentate niche. J Neurosci 31:11472-83
Nomura, Tadashi; Goritz, Christian; Catchpole, Timothy et al. (2010) EphB signaling controls lineage plasticity of adult neural stem cell niche cells. Cell Stem Cell 7:730-43

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