Loss-of-function mutations in members of the neuroligin (NL) family of trans-synaptic cell adhesion molecules have been implicated in human autism and mental retardation. Animal models of autism have been severely limited, but these human genetic findings provide a novel path to develop bona fide mouse models of at least a subtype of human autism or mental retardation. NLs are postsynaptic transmembrane proteins that bind presynaptic beta-neurexins to induce formation of excitatory and inhibitory synapses and to control excitatory/inhibitory (E/I) synapse balance in cultured neurons. Alterations in E/I balance have been proposed as important in pathogenesis of autism and mental retardation. The precise role of NL in vivo and in neurobehavioral abnormalities in autism and mental retardation, however, remains to be determined. We will determine the role of neuroligin in vivo using electrophysiologic and behavioral characterization of NL knockout, human disease mutation knockin, and, in follow-up studies, conditional knockout mice. The driving hypothesis is that mice deficient in NL genes, or carrying known disease-linked mutations in NL, will exhibit behavioral differences consistent with those in human autism or mental retardation, and that these behavioral differences will be associated with specific abnormalities in E/I balance or synaptic function in cortical circuits in vivo. The following specific aims will be addressed: 1. To determine whether NL3 disease-linked mutation or deletion of NL3 result in autism and mental retardation-related behavioral abnormalities. 2. To determine whether deletion of NL3 or NL3 disease-linked mutations result in altered excitatory and inhibitory synaptic connectivity and function. 3. To determine whether deletion of NL3 or NL3 disease-linked mutations alter the threshold for inducing NMDA-receptor-dependent synaptic plasticity in the hippocampus.

Public Health Relevance

Autism spectrum disorder and mental retardation are common, debilitating disorders involving social interaction or cognitive function with clinical overlap in a subset of patients. Recently, loss-of-function mutations in members of the Neuroligin family of trans-synaptic cell adhesion molecules have been implicated in human autism and mental retardation. Mice with genetic alterations of Neuroligin will be characterized as potential animal models of autism and mental retardation in an effort to better understand the cause and treatment of these debilitating disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Developmental Brain Disorders Study Section (DBD)
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Asanuma, Chiiko
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University of Texas Sw Medical Center Dallas
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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
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
Haws, M E; Kaeser, P S; Jarvis, D L et al. (2012) Region-specific deletions of RIM1 reproduce a subset of global RIM1ýý(-/-) phenotypes. Genes Brain Behav 11:201-13
Speed, Haley E; Blaiss, Cory A; Kim, Ahleum et al. (2012) Delayed reduction of hippocampal synaptic transmission and spines following exposure to repeated subclinical doses of organophosphorus pesticide in adult mice. Toxicol Sci 125:196-208
Lewis, Alan S; Vaidya, Sachin P; Blaiss, Cory A et al. (2011) Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. J Neurosci 31:7424-40
Blundell, Jacqueline; Blaiss, Cory A; Lagace, Diane C et al. (2011) Block of glucocorticoid synthesis during re-activation inhibits extinction of an established fear memory. Neurobiol Learn Mem 95:453-60
Bangash, M Ali; Park, Joo Min; Melnikova, Tatiana et al. (2011) Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism. Cell 145:758-72
Netzer, William J; Powell, Craig; Nong, Yi et al. (2010) Lowering beta-amyloid levels rescues learning and memory in a Down syndrome mouse model. PLoS One 5:e10943
Blundell, Jacqueline; Blaiss, Cory A; Etherton, Mark R et al. (2010) Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J Neurosci 30:2115-29
Blundell, Jacqueline; Kaeser, Pascal S; Sudhof, Thomas C et al. (2010) RIM1alpha and interacting proteins involved in presynaptic plasticity mediate prepulse inhibition and additional behaviors linked to schizophrenia. J Neurosci 30:5326-33

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