During the development of a child, most brain cells are generated before birth. There is one group of brain cells, however, that are generated in large numbers in infancy. This occurs in a brain region called the hippocampus. These cells are important for the normal development of memory, cognition and language, and disruption of these cells is present in children with autism. Disruption of these cells may also contribute to the prevalence of epilepsy in children with autism. Although it makes sense that these cells are responsible for key features of autism, children with the disease exhibit changes in many other parts of the brain as well. Our limited understanding of which changes are important, unfortunately, has slowed progress in the field. In the present proposal, therefore, we will examine the impact of eliminating a gene known to be involved in autism on these late-generated cells. These studies will reveal whether selectively disrupting these cells can reproduce features of autism. Demonstrating that these cells play an important role in the development of autism (or associated conditions like epilepsy), will provide a compelling rationale to develop new therapies to protect these vulnerable cells. In addition, since these cells are born so late in development, and are actually produced through childhood and into adulthood, it may be possible to prevent the disruption of cells born after a diagnosis of autism and thus allow the brain to naturally restore itself. It is our hope that these studies will move us closer to developing new and more effective treatments for autism.

Public Health Relevance

The proposed studies seek to better elucidate the causes of autism by determining whether selective disruption of late-generated neurons - specifically hippocampal dentate granule cells - contributes to key features of autism. This will be achieved using a novel combination of transgenic mice to selectively eliminate a gene implicated in autism from these late-generated neurons. Significantly, although the proximal cause of autism remains to be determined in most cases, the late generation of these neurons (in the late embryonic period and in infancy) may make them uniquely vulnerable to a variety of insults faced by the newborn child (e.g. infection). The proposal will also examine the role of granule cells in the development of epilepsy, the condition most commonly associated with autism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065020-02
Application #
7816937
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Mamounas, Laura
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$371,250
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Hosford, Bethany E; Rowley, Shane; Liska, John P et al. (2017) Ablation of peri-insult generated granule cells after epilepsy onset halts disease progression. Sci Rep 7:18015
Rowley, Shane; Sun, Xiaofei; Lima, Isabel V et al. (2017) Cannabinoid receptor 1/2 double-knockout mice develop epilepsy. Epilepsia 58:e162-e166
LaSarge, Candi L; Pun, Raymund Y K; Muntifering, Michael B et al. (2016) Disrupted hippocampal network physiology following PTEN deletion from newborn dentate granule cells. Neurobiol Dis 96:105-114
Hester, Michael S; Hosford, Bethany E; Santos, Victor R et al. (2016) Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain. Exp Neurol 280:1-12
Hosford, Bethany E; Liska, John P; Danzer, Steve C (2016) Ablation of Newly Generated Hippocampal Granule Cells Has Disease-Modifying Effects in Epilepsy. J Neurosci 36:11013-11023
Wulsin, Aynara C; Solomon, Matia B; Privitera, Michael D et al. (2016) Hypothalamic-pituitary-adrenocortical axis dysfunction in epilepsy. Physiol Behav 166:22-31
Jiang, Yifei; Tong, Dongyi; Hofacer, Rylon D et al. (2016) Long-term Fate Mapping to Assess the Impact of Postnatal Isoflurane Exposure on Hippocampal Progenitor Cell Productivity. Anesthesiology 125:1159-1170
LaSarge, Candi L; Santos, Victor R; Danzer, Steve C (2015) PTEN deletion from adult-generated dentate granule cells disrupts granule cell mossy fiber axon structure. Neurobiol Dis 75:142-50

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