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. We propose to create novel autism model mouse lines. We will produce both conditional and reversible knockouts as well as global, complete and isoform specific knockouts of autism candidate genes to mimic human autism mutations. Our progress to date is substantial in that we have now demonstrated of several mutant mouse models related to autism, thereby establishing these lines for our studies and for the general neuroscience community. We now propose to expand these novel autism model mouse lines and perform initial molecular, biochemical, electrophysiologic and behavioral characterization. In particular, we will measure behaviors corresponding to each of the three core symptom domains in autism spectrum disorder in these mouse lines. The result will be novel genetic model mouse lines of autism, behavioral relevance of the model to autism, and initial studies on brain function using electrophysiology to understand effects on cortical synapses.

Public Health Relevance

Our goal is to better understand genetic causes of human autism and to use animal models of such causes to identify treatments. This 5-year R01 proposal capitalizes on our significant progress in creating animal models of autism and will allow us to rapidly advance this field. The marriage of our understanding of brain pathology with behavioral abnormalities in these mice will lead to testable hypotheses regarding pharmacologic treatment of autism symptoms in the model and ultimately in autistic patients.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
3R01HD069560-02S1
Application #
8546632
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Kau, Alice S
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$99,773
Indirect Cost
$37,023
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
Escamilla, Christine Ochoa; Filonova, Irina; Walker, Angela K et al. (2017) Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature 551:227-231
Celen, Cemre; Chuang, Jen-Chieh; Luo, Xin et al. (2017) Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. Elife 6:
Jaramillo, Thomas C; Escamilla, Christine Ochoa; Liu, Shunan et al. (2017) Genetic background effects in Neuroligin-3 mutant mice: Minimal behavioral abnormalities on C57 background. Autism Res :
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
Hussain, Rehana Z; Miller-Little, William A; Lambracht-Washington, Doris et al. (2017) Laquinimod has no effects on brain volume or cellular CNS composition in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. J Neuroimmunol 309:100-110
Fernandes, Darren J; Ellegood, Jacob; Askalan, Rand et al. (2017) Spatial gene expression analysis of neuroanatomical differences in mouse models. Neuroimage 163:220-230
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
Powell, Craig M (2017) Neuroscience: Mum's bacteria linked to baby's behaviour. Nature 549:466-467
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

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