Disorders of cognitive, social and perceptual functions are associated with abnormalities of cortical synaptic circuit development and plasticity. There is a strong genetic disposition to such diseases, but the precise causes are unknown. Microdeletions in chromosome 15q24 are associated with a syndrome that features autism. A recent study of 15q24 microdeletion syndrome identified a minimal deletion interval that contains only four genes that are expressed in brain, among which, SEMA7A stands apart as highly relevant to sensory dysfunctions associated with the syndrome. Sema7A is an atypical member of the Semaphorin family of guidance cues: it is membrane-anchored by a GPI-linkage;it is expressed principally postnatally in the nervous system;and it can promote axon extension in a ?1 integrin-dependent manner. These findings point to the idea that Sema7A has roles in late stages of brain development distinct from the customary Semaphorin-Plexin interactions that generate axon repulsion during embryonic development, but this has not been explored. Our data show that Sema7A is particularly enriched in somatosensory (S1) cortex at a time when synapses develop and sensory experience drives the refinement of connectivity. Accordingly, we hypothesize that Sema7A functions in the maturation and fine-tuning of cortical microcircuitry that occurs during early postnatal development. In mouse S1 barrel cortex our preliminary data show that when Sema7A is genetically ablated thalamocortical axons reach layer IV, but their synapses fail to mature functionally and their postsynaptic dendritic targets fil to orient their arbors appropriately. In contrast, somatosensory maps in subcortical centers are normal. These data outline an entirely novel molecular contribution to the functional and structural development of cortical sensory maps, the absence of which may perturb information processing through cortical microcircuits that in turn, produce symptoms relevant to 15q24 microdeletion syndrome. Our preliminary data serve as the basis for the hypothesis that Sema7A is essential for normal S1 maturation and function.

Public Health Relevance

The proposed studies will define novel biological roles of an atypical Semaphorin that is deleted in 15q24 Microdeletion Syndrome, a syndrome that shares features with Autism Spectrum Disorders (ASD);advance understanding of the molecular control of cortical sensory map organization and development;and reveal new insights into developmental alterations in cortical circuitry that may underlie cognitive and perceptual impairments associated with ASD-related pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH095229-01A1
Application #
8400750
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (91))
Program Officer
Panchision, David M
Project Start
2012-07-19
Project End
2014-06-30
Budget Start
2012-07-19
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$423,750
Indirect Cost
$173,750
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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