# Conditional deletion of neurexin-2 impaired behavioral flexibility to alterations in action–outcome contingency

## TL;DR

Deleting a brain protein called neurexin-2 in mice caused problems with adapting to changes in how actions lead to outcomes, suggesting a role in behavioral flexibility.

## Contribution

This study shows that two different ways of deleting neurexin-2 in specific brain regions lead to behavioral inflexibility in mice.

## Key findings

- Mice with neurexin-2 deletion failed to adjust between goal-directed and habitual actions when outcomes changed.
- Emx1-driven neurexin-2 deletion caused reversal learning deficits in a maze task.
- Two distinct deletion methods both impaired behavioral flexibility in response to altered action-outcome contingencies.

## Abstract

Neurexins (Nrxns) are critical for synapse organization and their mutations have been documented in autism spectrum disorder, schizophrenia, and epilepsy. We recently reported that conditional deletion of Nrxn2, under the control of Emx1Cre promoter, predominately expressed in the neocortex and hippocampus (Emx1-Nrxn2 cKO mice) induced stereotyped patterns of behavior in mice, suggesting behavioral inflexibility. In this study, we investigated the effects of Nrxn2 deletion through two different conditional approaches targeting presynaptic cortical neurons projecting to dorsomedial striatum on the flexibility between goal-directed and habitual actions in response to devaluation of action–outcome (A–O) contingencies in an instrumental learning paradigm or upon reversal of A–O contingencies in a water T-maze paradigm. Nrxn2 deletion through both the conditional approaches induced an inability of mice to discriminate between goal-directed and habitual action strategies in their response to devaluation of A–O contingency. Emx1-Nrxn2 cKO mice exhibited reversal learning deficits, indicating their inability to adopt new action strategies. Overall, our studies showed that Nrxn2 deletion through two distinct conditional deletion approaches impaired flexibility in response to alterations in A–O contingencies. These investigations can lay the foundation for identification of novel genetic factors underlying behavioral inflexibility.