Autism spectrum disorders (ASDs) are common, debilitating disorders affecting social interaction, communication, and repetitive behaviors. Recent genetic findings have identified mutations in synaptic cell adhesion genes and genes encoding their interacting protein partners at central synapses as genetic causes of autism spectrum disorders. This proposal will characterize novel and innovative autism mouse models that allow for brain development to take place with a genetic mutation. These particular models allow for reversal of the mutation at various times during brain development and ultimately in specific brain regions. The goal is to narrow the developmental critical period during which such mutations lead to altered brain function and atypical behavior. This information will allow scientists to focus specifically on the time periods and brain regions critical for generation of atypical behavior. In addition, these studies will substantiate feasibility of genetic and certain pharmacological approaches to treatment of a genetic form of autism. Progress to date is substantial in that the genetically reversible mutant mouse models related to autism have been established and characterization has begun.

Public Health Relevance

It is critical to better understand genetic causes of human autism and to use animal models of such causes to identify treatments. This 5-year R01 renewal proposal capitalizes on significant progress in creating and characterizing animal models of autism that will allow us to rapidly advance this field. Novel genetic animal models have been created that now allow for precise control over genetic mutations and reversal of these genetic mutations at any time during development of the brain and in any brain region allowing extensive characterization of these new models for a complete understanding of when during brain development things go awry and where in the brain things go awry.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD069560-07
Application #
9251872
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (57)M)
Program Officer
Kau, Alice S
Project Start
2011-09-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
7
Fiscal Year
2017
Total Cost
$627,293
Indirect Cost
$240,075
Name
University of Texas Sw Medical Center Dallas
Department
Neurology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Goodspeed, Kimberly; Newsom, Cassandra; Morris, Mary Ann et al. (2018) Pitt-Hopkins Syndrome: A Review of Current Literature, Clinical Approach, and 23-Patient Case Series. J Child Neurol 33:233-244
Jaramillo, Thomas C; Escamilla, Christine Ochoa; Liu, Shunan et al. (2018) Genetic background effects in Neuroligin-3 mutant mice: Minimal behavioral abnormalities on C57 background. Autism Res 11:234-244
Jaramillo, Thomas C; Speed, Haley E; Xuan, Zhong et al. (2017) Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function. Autism Res 10:42-65
Escamilla, Christine Ochoa; Filonova, Irina; Walker, Angela K et al. (2017) Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature 551:227-231
Araujo, Daniel J; Toriumi, Kazuya; Escamilla, Christine O et al. (2017) Foxp1 in Forebrain Pyramidal Neurons Controls Gene Expression Required for Spatial Learning and Synaptic Plasticity. J Neurosci 37:10917-10931
Celen, Cemre; Chuang, Jen-Chieh; Luo, Xin et al. (2017) Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. Elife 6:
Powell, Craig M (2016) Autism Screening or Smoke Screen and Mirrors? JAMA Neurol 73:386-7
Jaramillo, Thomas C; Speed, Haley E; Xuan, Zhong et al. (2016) Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism. Autism Res 9:350-75
Speed, Haley E; Kouser, Mehreen; Xuan, Zhong et al. (2015) Autism-Associated Insertion Mutation (InsG) of Shank3 Exon 21 Causes Impaired Synaptic Transmission and Behavioral Deficits. J Neurosci 35:9648-65
Latchney, Sarah E; Jaramillo, Thomas C; Rivera, Phillip D et al. (2015) Chronic P7C3 treatment restores hippocampal neurogenesis in the Ts65Dn mouse model of Down Syndrome [Corrected]. Neurosci Lett 591:86-92

Showing the most recent 10 out of 25 publications