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 have created a novel autism model mouse line based on deletion of neuroligin-1. These mice have selective, excessive repetitive behavioral abnormalities of potential relevance to autism. Our preliminary data strongly implicate a decrease in NMDA receptor function in the striatum as a cause of this repetitive behavior phenotype. We now propose experiments to examine the effect of deletion of this gene on cortico-striatal synaptic function in detail. Furthermore, we propose to selectively rescue/treat this phenotype using genetic and pharmacologic approaches. Thus, we will be able to directly connect a specific synapse in a specific brain region due to a specific molecular abnormality with an abnormal behavior, an important basic goal in neuroscience. These experiments will identify novel synaptic and circuit-level mechanisms for obsessive-compulsive disorder- like repetitive behaviors in general. In addition, we hope to identify novel treatment targets for these behaviors for a subset of autistic patients.
Our goal is to better understand genetic causes of human autism and to use animal models of such causes to identify treatments. This R01 proposal capitalizes on our recent progress examining a novel genetic autism- relevant model. This model exhibits excessive stereotyped repetitive behaviors characteristic of autism. Our experiments will directly link abnormalities in brain function in a specific brain region with these abnormal behaviors and allow us to identify novel treatment targets for a subset of autism and perhaps other disorders with obsessive-compulsive-like behavioral differences. Ultimately, such treatments could be tested directly in patients.
|Powell, Craig M (2016) Autism Screening or Smoke Screen and Mirrors? JAMA Neurol 73:386-7|
|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|
|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|
|Espinosa, Felipe; Xuan, Zhong; Liu, Shunan et al. (2015) Neuroligin 1 modulates striatal glutamatergic neurotransmission in a pathway and NMDAR subunit-specific manner. Front Synaptic Neurosci 7:11|
|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|
|SurÃs, Alina; Smith, Julia; Powell, Craig et al. (2013) Interfering with the reconsolidation of traumatic memory: sirolimus as a novel agent for treating veterans with posttraumatic stress disorder. Ann Clin Psychiatry 25:33-40|
|Kouser, Mehreen; Speed, Haley E; Dewey, Colleen M et al. (2013) Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission. J Neurosci 33:18448-68|
|Rojas, Julio C; Banerjee, Chirantan; Siddiqui, Fazeel et al. (2013) Pearls and oy-sters: acute ischemic stroke caused by atypical thrombotic thrombocytopenic purpura. Neurology 80:e235-8|
|Petrik, David; Jiang, Yindi; Birnbaum, Shari G et al. (2012) Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule. FASEB J 26:3148-62|
|Haws, M E; Kaeser, P S; Jarvis, D L et al. (2012) Region-specific deletions of RIM1 reproduce a subset of global RIM1Î±(-/-) phenotypes. Genes Brain Behav 11:201-13|
Showing the most recent 10 out of 12 publications