The 22q11 deletion syndrome (22q11DS), also known as velocardiofacialsyndrome or DiGeorge syndrome, is the most common microdeletion syndrome in humans. Cognitive deficits occur in virtually all patients with 22q11DS, and schizophrenia or schizoaffective disorder develops in approximately 30% during their adolescence or early adulthood. Deficits in learning and memory have been identified in patients with 22q11DS and in Df(16)1/+ mice, the mouse model of this disease. However, the cellular mechanisms and gene(s) responsible for these deficits remain unknown. Recently, we discovered that long-term potentiation (LTP) of synaptic transmission, a major form of synaptic plasticity and cellular substrate of certain forms of learning and memory, is substantially altered in Df(16)1/+ mice. We determined that these changes are caused by the abnormal presynaptic function at excitatory synapses. Further experiments revealed that the increase in presynaptic function was caused by the deletion of 2 genomic regions within the large microdeletion, Df(16)2 and Df(16)5. Screening of mice with deletions of individual genes within the Df(16)2 region revealed that a deletion of the microRNA-processing gene Dgcr8 upregulates sarco(endo)plasmic reticulum ATP-ase 2 (SERCA2) in excitatory neurons and leads to abnormal neurotransmitter release and LTP. The identity of the culprit gene within the Df(16)5 region remains unknown. In this application, we propose to identify the microRNA(s) responsible for the upregulation of SERCA2 and the defects in synaptic plasticity by using electrophysiological and molecular tools, two-photon laser scanning microscopy, and two-photon uncaging. Using knockout mice recently developed in our laboratory, we will also identify the culprit gene(s) within the Df(16)5 region. Finally, we propose to test the role of the endoplasmic reticulum in presynaptic phenotypes of mouse models of 22q11DS. This information will provide a framework for the future development of therapeutic interventions to prevent or alleviate cognitive deficits in patients with 22q11DS.

Public Health Relevance

Heterozygous deletions within the 22q11 chromosome substantially increase an individual's risk for schizophrenia. Cognitive function is characteristically impaired in patients and mouse models that carry these deletions. To better understand these deficits and find the causal genes and downstream signaling pathways, we will investigate the mechanisms of synaptic abnormalities in mutant mice that model 22q11 deletion syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH095810-02
Application #
8526567
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2012-08-08
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$420,000
Indirect Cost
$180,000
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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Devaraju, P; Yu, J; Eddins, D et al. (2017) Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium. Mol Psychiatry 22:1313-1326
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Diouf, Barthelemy; Devaraju, Prakash; Janke, Laura J et al. (2016) Msh2 deficiency leads to dysmyelination of the corpus callosum, impaired locomotion, and altered sensory function in mice. Sci Rep 6:30757
Gingras, Sebastien; Earls, Laurie R; Howell, Sherie et al. (2015) SCYL2 Protects CA3 Pyramidal Neurons from Excitotoxicity during Functional Maturation of the Mouse Hippocampus. J Neurosci 35:10510-22
Earls, Laurie R; Westmoreland, Joby J; Zakharenko, Stanislav S (2014) Non-coding RNA regulation of synaptic plasticity and memory: implications for aging. Ageing Res Rev 17:34-42
Earls, Laurie R; Zakharenko, Stanislav S (2014) A Synaptic Function Approach to Investigating Complex Psychiatric Diseases. Neuroscientist 20:257-71

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