Recent evidence suggests that abnormalities in synaptic transmission may underlie the pathogenesis of several neuropsychiatric disorders. A better understanding of normal and aberrant synaptic function may provide improved detection and treatment strategies, thereby reducing overall disease burden. Towards these ends, the use of gene targeting in mouse has provided a unique opportunity to create laboratory animals with similar mutations to human patients that have clinically defined neuropsychiatric disorders. Thorough analysis of these mutant mice, both at the behavioral and cellular level, can thus provide a wealth of information about potential mechanisms of disease formation as well as the relationship between gene dysfunction and abnormal behavior. Evidence from a variety of human genetic association studies has highlighted the functional relevance of synaptic cell adhesion molecules (SCAMs) in neuropsychiatric disorders including autism, schizophrenia and obsesive compulsive disorder. The Neuroligin (NL)/Neurexin complex, a prototypical SCAM pair, has been implicated in excitatory and inhibitory synaptic function. In an attempt to further explore NL function, a mouse was made with a point mutation (R451C) in the NL3 gene to mimic a mutation associated with autism in a human genetics study. The goal of this proposal is to study this mutant mouse from both behavioral and synaptic perspectives, with the hope of linking abnormal behaviors to specific underlying circuit and synaptic abnormalities. Causality will then be established through attempts to ameliorate behavioral phenotypes by addressing the underlying synaptic deficits. I have chosen to focus on functional cognitive deficits, particularly cognitive flexibility, in NL3R451C mutants, as these represent a core, debilitating feature of many neuropsychiatric disorders and their underlying synaptic mechanisms have thus far received little attention. Preliminary data suggest that NL3R451C mutants have severely impaired cognitive flexibility. During the mentored phase, I will employ viral injections to localie which synapses require NL3 function to maintain cognitive flexibility. In addition, I will employ optogenetic recruitment of cortical afferent populations in the acute slice to explore abnormalities of corticostriatal synaptic transmission in the dorsal striatum of NL3R451C mutant mice. For the independent phase, I wil first explore potential abnormalities in synaptic plasticity in NL3R451C mutants. After a thorough description of the alterations of both basal transmission and activity-dependent plasticity found in the striatum of mutants, I will attempt to link these synaptic deficiencies to the observed abnormalities in cognitive flexibility through the use of cel-type and regional optogenetic manipulations. I anticipate that this proposal will uncover interesting information regarding the synaptic basis of cognitive flexibility and how perturbations of synaptic transmission in NL3R451C mutants result in rigid behavioral output. Furthermore, it will provide a template for my future studies into how other synaptic molecules mediate cognitive function.

Public Health Relevance

Synapses are specialized junctions that mediate communication between different brain regions. Recent evidence suggests that abnormalities of the synapse may be central to a range of neuropsychiatric disorders. This proposal will use cutting-edge methodologies to explore synaptic dysfunction and its relationship to altered behavior in hopes of shedding light on the causes of neuropsychiatric disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Career Transition Award (K99)
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Special Emphasis Panel (ZMH1-ERB-L (06))
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Desmond, Nancy L
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Stanford University
Schools of Medicine
United States
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Fuccillo, Marc V; Rothwell, Patrick E; Malenka, Robert C (2016) From Synapses to Behavior: What Rodent Models Can Tell Us About Neuropsychiatric Disease. Biol Psychiatry 79:4-6
Fuccillo, Marc V; Földy, Csaba; Gökce, Özgün et al. (2015) Single-Cell mRNA Profiling Reveals Cell-Type-Specific Expression of Neurexin Isoforms. Neuron 87:326-40
Rothwell, Patrick E; Hayton, Scott J; Sun, Gordon L et al. (2015) Input- and Output-Specific Regulation of Serial Order Performance by Corticostriatal Circuits. Neuron 88:345-56
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