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.
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.
|Jaramillo, Thomas C; Speed, Haley E; Xuan, Zhong et al. (2016) Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function. Autism Res :|
|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|
|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|
|Speed, Haley E; Masiulis, Irene; Gibson, Jay R et al. (2015) Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling. PLoS One 10:e0140638|
|Ellegood, J; Anagnostou, E; Babineau, B A et al. (2015) Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity. Mol Psychiatry 20:118-25|
|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|
|Jaramillo, Thomas C; Liu, Shunan; Pettersen, Ami et al. (2014) Autism-related neuroligin-3 mutation alters social behavior and spatial learning. Autism Res 7:264-72|
|Latchney, Sarah E; Masiulis, Irene; Zaccaria, Kimberly J et al. (2014) Developmental and adult GAP-43 deficiency in mice dynamically alters hippocampal neurogenesis and mossy fiber volume. Dev Neurosci 36:44-63|
|Haws, Michael E; Jaramillo, Thomas C; Espinosa, Felipe et al. (2014) PTEN knockdown alters dendritic spine/protrusion morphology, not density. J Comp Neurol 522:1171-90|
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