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)
Institute
National Institute of Mental Health (NIMH)
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
2002-03-01
Project End
2019-06-30
Budget Start
2014-07-15
Budget End
2015-06-30
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
Treffy, Randall William; Collins, David; Hoshino, Natalia et al. (2016) Ephrin-B/EphB Signaling Is Required for Normal Innervation of Lingual Gustatory Papillae. Dev Neurosci 38:124-38
Robichaux, Michael A; Chenaux, George; Ho, Hsin-Yi Henry et al. (2016) EphB1 and EphB2 intracellular domains regulate the formation of the corpus callosum and anterior commissure. Dev Neurobiol 76:405-20
Zhu, Xiao-Na; Liu, Xian-Dong; Sun, Suya et al. (2016) Ephrin-B3 coordinates timed axon targeting and amygdala spinogenesis for innate fear behaviour. Nat Commun 7:11096
Zhu, Xiao-Na; Liu, Xian-Dong; Zhuang, Hanyi et al. (2016) Amygdala EphB2 Signaling Regulates Glutamatergic Neuron Maturation and Innate Fear. J Neurosci 36:10151-62
Bhatia, Shilpa; Baig, Nimrah A; Timofeeva, Olga et al. (2015) Knockdown of EphB1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization. Oncotarget 6:8929-46
Zhang, Gu; Brady, John; Liang, Wei-Ching et al. (2015) EphB4 forward signalling regulates lymphatic valve development. Nat Commun 6:6625
Villar-Cerviño, Verona; Kappeler, Caroline; Nóbrega-Pereira, Sandrina et al. (2015) Molecular mechanisms controlling the migration of striatal interneurons. J Neurosci 35:8718-29
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
Bouché, Elisabeth; Romero-Ortega, Mario I; Henkemeyer, Mark et al. (2013) Reelin induces EphB activation. Cell Res 23:473-90

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