The objective of this proposal is to advance our limited understanding of the pathophysiology of autism spectrum disorders (ASDs), a group of prevalent and devastating neuropsychiatric conditions. This will be accomplished by studying mice carrying a genetic mutation (neuroligin-3 R451C) that is highly penetrant and specifically associated with ASDs in humans. Preliminary data indicate these mice develop more automated and stereotyped behavior in a motor learning task, a phenotype that may represent a behavioral indicator, as it is also associated with other ASD-related genetic mutations. I propose to investigate the function of the striatum and its synaptic inputs from frontal cortex, a neural circuit that may contribute to the aforementioned behavioral change, as well as other forms of inflexible and habitual behavior associated with ASDs. Using optogenetics to specifically stimulate this neural circuit with light, the functional properties of frontostriatal synapses will be examined in neuroligin-3 R451C mutant mice. Preliminary data indicates the feasibility of this approach for assaying synaptic function in a brain slice preparation. The capacity of frontostriatal synapses to undergo activity-dependent plasticity will also be assessed. Finally, physiology and behavior will be examined following molecular manipulation of neuroligin-3 expression within this neural circuit. In total, these experiments attempt to determine the mechanism by which mutated gene and its product (neuroligin-3 R451C) influence the function of frontostriatal circuits, using a combination of experimental approaches that integrate multiple levels of brain function (molecules, cells, circuits and behavior).
Despite the identification of genetic mutations associated with autism spectrum disorders (ASDs), we do not yet understand how these mutations alter brain function and produce the changes in behavior that define ASDs. The proposed experiments will determine whether one such mutation causes abnormal function in the parts of the brain that produce repetitive and stereotyped behaviors. Identifying a malfunction in this specific brain circuit may lead to new treatments that reduce or prevent the symptoms of ASDs.
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| Rothwell, Patrick E; Fuccillo, Marc V; Maxeiner, Stephan et al. (2014) Autism-associated neuroligin-3 mutations commonly impair striatal circuits to boost repetitive behaviors. Cell 158:198-212 |
| Rothwell, Patrick E; Lammel, Stephan (2013) Illuminating the opponent process: cocaine effects on habenulomesencephalic circuitry. J Neurosci 33:13935-7 |
| Grueter, Brad A; Rothwell, Patrick E; Malenka, Robert C (2012) Integrating synaptic plasticity and striatal circuit function in addiction. Curr Opin Neurobiol 22:545-51 |
| Lim, Byung Kook; Huang, Kee Wui; Grueter, Brad A et al. (2012) Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487:183-9 |
