Synaptic adhesion molecules (SAMs) are implicated in the formation, specification and maintenance of neuronal connections. Pathway analyses of mutations associated with neuropsychiatric disease implicate synaptic dysfunction as a pathophysiological mechanism, making SAMs important candidates for deeper functional exploration. Studies in humans suggest that Neurexin1? (Nrxn1?), a presynaptically-localized organizer of synaptic architecture, is a partially penetrant genetic risk factor for multiple neuropsychiatric diseases displaying altered goal-directed processing. We demonstrate that Nrxn1? mutants exhibit robust changes in how rewards shape future choices, and may provide a neural circuit framework for understanding inflexible and perseverative actions associated with many neuropsychiatric disorders. This proposal therefore employs genetic, viral, electrophysiological and behavioral approaches in mice to explore how Nrxn1? mutations lead to neural circuit changes capable of altering reward processing. Nrxn1? is widely expressed in brain, but exhibits peak levels throughout cortex and thalamus, sites whose extensive projections to striatum regulate reward processing. Using retrograde-transported viruses or region-specific Cre transgenic mice, together with our Nrxn1? conditional allele, we will ablate Nrxn1? from cortex, thalamus or projection neurons targeting specific striatal compartments. Mice will be tested in our goal-directed tasks to reveal neural circuits wherein Nrxn1? dysfunction precipitates reward abnormalities. To elucidate how these circuits are physiologically altered in Nrxn1? mutants, we will electrophysiologically probe the synaptic strength of cortical and thalamic inputs to the DMS. Preliminary results suggest enhancements in basal excitatory synaptic drive onto both DMS spiny neuron subtypes. Using optogenetic-mediated afferent recruitment and field-normalized synaptic efficacy measures, we will determine input-specific synaptic strength changes in Nrxn1? mutants. Furthermore, we will employ sparse infections of a fused channelrhodopsin-Cre virus into our Nrxn1? conditionals together with acute slice electrophysiology to permit selective recruitment of Nrxn1?-null terminals, thereby gaining mechanistic insight into the cell-autonomous anatomical and synaptic abnormalities caused by Nrxn1? loss-of-function. The mere presence of circuit-specific physiological changes in Nrxn1? mutants does not functionally implicate them in goal-directed dysfunction. To prove this, and broaden our analyses of Nrxn1? disruption to a circuit level, we will use viral-based techniques for activity modulation to see whether mimicking Nrxn1?-associated physiological changes in wildtype mice can produce mutant-like GDB performance or whether counteracting these physiological alterations in mutant mice can suppress the mutant behavioral phenotype. Together, the proposed work investigates how goal-directed neural systems are altered by the synaptic and circuit changes accompanying Nrxn1? perturbation, and may provide a foundation for understanding common circuit changes in reward processing - a key step for circuit-specific intervention.

Public Health Relevance

Goal-directed behavior is impaired in many neuropsychiatric diseases, significantly affecting daily function. Studies in humans suggest that Neurexin1?, a molecule important for organizing neuronal connections, is a genetic risk factor for multiple neuropsychiatric diseases exhibiting deficits in goal-directed behavior. This proposal uses a range of genetic, molecular, physiological, and behavioral methods to explore how goal- directed neural systems are altered by Neurexin1? dysfunction, potentially providing a foundation for future therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH115030-03
Application #
9816575
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Rossi, Andrew
Project Start
2017-11-15
Project End
2022-10-31
Budget Start
2019-11-01
Budget End
2020-10-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Neurosciences
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104