Down syndrome (DS), caused by trisomy for human chromosome 21 (Hsa21), is the most common genetically defined cause of intellectual disability. Structural abnormalities that are thought to contribute to learning problems are seen in the cerebellum and hippocampus of people with the condition. Treatments to correct these parts of the brain would tangibly improve the lives of children and young adults with DS and would allow them to better integrate into society. We recently showed that a single injection on the day of birth with the Sonic Hedgehog (Shh) agonist, SAG 1.1, permanently normalizes the size and gross anatomy of the cerebellum, leads to better adult spatial problem solving, and restores electrophysiological correlates of learning in the CA1-hippocampal subfield of the Ts65Dn mouse model of DS. A number of questions remain before this finding can be translated to therapy for people. Whether improvements in hippocampal behavior &physiology occur through Shh-induced normalization of cerebellar structure or via direct stimulation with Shh is not known. Another restraint on advancing Shh treatments to the clinic is the very wide range of effects of this potent growth factor, making systemic application in people problematic. A more confined method of drug delivery might limit side effects. Another approach would be to understand which Hsa21 genes act to downregulate the Shh pathway response in cerebellum, which might suggest more "druggable" targets. The experiments proposed here will first screen Shh responses with an Hsa21 Gene Expression clone-set of 169 cDNAs, 149 of which are highly conserved between human and mouse and twenty that are human specific. Genes that significantly decrease Shh pathway activation in the LIGHT2 assay will be evaluated in additional Shh-sensitive assays to assure that they generalize across different biological systems (Specific Aim 1). Next, we will determine how region-specific expression of Shh in the Ts65Dn brain affects hippocampal function. Using a conditional "temporal-spatial" genetics approach that will allow us to increase Shh expression at birth for a 24h period selectively within the Purkinje cells of the cerebellum, or within the hippocampus, we will determine whether cerebellar Shh expression is necessary and/or sufficient to correct the behavior &physiology of adult Ts65Dn mice in hippocampal tests or whether Shh actions in additional parts of the brain are required (Specific Aim 2).

Public Health Relevance

Down syndrome affects thousands of families annually, producing substantial financial and emotional costs. Advent of treatments to improve daily learning and memory in children with DS like those being developed in the present application would alleviate much of this burden.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD082614-01
Application #
8808144
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Krotoski, Danuta
Project Start
2014-09-22
Project End
2016-08-31
Budget Start
2014-09-22
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$243,000
Indirect Cost
$93,000
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Dutka, Tara; Hallberg, Dorothy; Reeves, Roger H (2015) Chronic up-regulation of the SHH pathway normalizes some developmental effects of trisomy in Ts65Dn mice. Mech Dev 135:68-80