Neural cell adhesion molecule NCAM (11q23) performs vital roles in learning and memory by regulatingguidance of CMS axons. NCAM merits study as a schizophrenia vulnerability gene, as NCAMpolymorphisms are associated with neurocognitive impairment in a schizophrenia population (CATIE).Moreover, a soluble NCAM fragment consisting of the entire extracellular region (NCAM-EC) isoverexpressed in schizophrenic brain, and is released from normal neurons by proteolytic cleavage(ectodomain shedding) by a metalloprotease with properties of an ADAM (a disintegrin and metalloprotease).Excess NCAM shedding in the prefrontal cortex (RFC) was modeled in NCAM-EC transgenic mice, whichrevealed a striking decrease in synapses of GABAergic interneurons, including basket cells that regulatepyramidal cell output and synchrony. NCAM-EC mice display behavioral abnormalities associated withneurotransmission defects, including hyperlocomotion, stereotypies, decreased sensory gating and fearconditioning. It is hypothesized that NCAM regulates the excitatory/inhibitory balance between basketinterneurons and pyramidal cells in the RFC, and that dysregulation of NCAM by excessive sheddingperturbs synaptic connectivity, thus altering cortical circuitry and synchrony of pyramidal cell groupsimportant for neurocognition. GABAergic function may be compromised in schizophrenia, but it is not knownif GABAergic dysfunction reflects altered development of cortical circuitry. It will be determined if there aredevelopmentally regulated changes in dendritic/axonal arborization and synaptogenesis of GABAergicinterneurons and pyramidal neurons in normal RFC,and whether NCAM dysregulation interferes withdevelopment in NCAM-EC and null mutant mice. NCAM shedding will be assessed during development inpost-mortem human brain and from individuals with schizophrenia. Cortical neuron cultures will be exploitedto identify the ADAM protease(s) responsible for normal NCAM shedding, to localize the NCAM cleavagesite, and to ascertain the role of NCAM shedding on neuronal process outgrowth and branching. Finally,behavioral testing in mice will assess whether NCAM-EC overexpression impairs executive functions suchas working memory, decreases gamma oscillatory activity, and alters sensitivity to GABA agonists in anxiety-like behavior and sensorimotor gating. This work will assist other center investigators in understandingdevelopment of GABAergic interneurons from early differentiation (Project 4), migration (Projects 4 and 5),and establishment of connections (this project) and will characterize a molecular substrate for abnormalneurocognitive functions in patients who are at risk or in early stages of schizophrenia (Projects 1 and3).These studies will illuminate a mechanism whereby NCAM contributes to GABAergic cortical circuitryrelevant to neurocognitive function, and will explore NCAM as a pathophysiological target for schizophreniavulnerability.
| Lyu, Ilwoo; Kim, Sun Hyung; Girault, Jessica B et al. (2018) A cortical shape-adaptive approach to local gyrification index. Med Image Anal 48:244-258 |
| Stephens, Rebecca L; Langworthy, Benjamin; Short, Sarah J et al. (2018) Verbal and nonverbal predictors of executive function in early childhood. J Cogn Dev 19:182-200 |
| Girault, Jessica B; Langworthy, Benjamin W; Goldman, Barbara D et al. (2018) The Predictive Value of Developmental Assessments at 1 and 2 for Intelligence Quotients at 6. Intelligence 68:58-65 |
| Tu, Liyun; Styner, Martin; Vicory, Jared et al. (2018) Skeletal Shape Correspondence Through Entropy. IEEE Trans Med Imaging 37:1-11 |
| Jha, Shaili C; Xia, Kai; Schmitt, James Eric et al. (2018) Genetic influences on neonatal cortical thickness and surface area. Hum Brain Mapp 39:4998-5013 |
| Wang, Yan; Ma, Guangkai; An, Le et al. (2017) Semisupervised Tripled Dictionary Learning for Standard-Dose PET Image Prediction Using Low-Dose PET and Multimodal MRI. IEEE Trans Biomed Eng 64:569-579 |
| Xia, K; Zhang, J; Ahn, M et al. (2017) Genome-wide association analysis identifies common variants influencing infant brain volumes. Transl Psychiatry 7:e1188 |
| Sadeghi, Neda; Gilmore, John H; Gerig, Guido (2017) Twin-singleton developmental study of brain white matter anatomy. Hum Brain Mapp 38:1009-1024 |
| Wei, Lifang; Cao, Xiaohuan; Wang, Zhensong et al. (2017) Learning-based deformable registration for infant MRI by integrating random forest with auto-context model. Med Phys 44:6289-6303 |
| Gao, Wei; Lin, Weili; Grewen, Karen et al. (2017) Functional Connectivity of the Infant Human Brain: Plastic and Modifiable. Neuroscientist 23:169-184 |
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