# Molecular and Circuit Mechanisms of Neurexin1-Mediated Goal-Directed Dysfunction

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $460,974

## Abstract

Project Summary
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 Neurexin1α (Nrxn1α), 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 Nrxn1α 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 Nrxn1α
mutations lead to neural circuit changes capable of altering reward processing. Nrxn1α 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 Nrxn1α conditional allele, we will ablate Nrxn1α from cortex, thalamus or projection neurons
targeting specific striatal compartments. Mice will be tested in our goal-directed tasks to reveal neural circuits
wherein Nrxn1α dysfunction precipitates reward abnormalities. To elucidate how these circuits are
physiologically altered in Nrxn1α 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 Nrxn1α mutants.
Furthermore, we will employ sparse infections of a fused channelrhodopsin-Cre virus into our Nrxn1α
conditionals together with acute slice electrophysiology to permit selective recruitment of Nrxn1α-null terminals,
thereby gaining mechanistic insight into the cell-autonomous anatomical and synaptic abnormalities caused by
Nrxn1α loss-of-function. The mere presence of circuit-specific physiological changes in Nrxn1α mutants does
not functionally implicate them in goal-directed dysfunction. To prove this, and broaden our analyses of Nrxn1α
disruption to a circuit level, we will use viral-based techniques for activity modulation to see whether mimicking
Nrxn1α-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 b...

## Key facts

- **NIH application ID:** 9816575
- **Project number:** 5R01MH115030-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Marc V Fuccillo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $460,974
- **Award type:** 5
- **Project period:** 2017-11-15 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9816575

## Citation

> US National Institutes of Health, RePORTER application 9816575, Molecular and Circuit Mechanisms of Neurexin1-Mediated Goal-Directed Dysfunction (5R01MH115030-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9816575. Licensed CC0.

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