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CNTN4, a Candidate Gene Associated with Autism Spectrum Disorders and Anorexia Nervosa, Has a Function in the Neurodevelopmental Trajectory of Cognitive Rigidity in Mice

Saturday, May 17, 2014
Atrium Ballroom (Marriott Marquis Atlanta)
A. Oguro-Ando, R. Molenhuis, L. de Visser, J. J. Sprengers, P. H. Burbach and M. J. Kas, Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands
Background: Cognitive rigidity is a major clinical relevant characteristic of various psychiatric illnesses, including autism spectrum disorders (ASD) and anorexia nervosa (AN). Understanding the developmental trajectory of neurobiological mechanisms underlying cognitive rigidity will be an important step to develop clinical treatment that may be relevant across these different psychiatric diagnoses. Both ASD and AN have a multifaceted symptomatology, however, they have overlapping features with respect to restricted behaviors and behavioral inflexibility. CNTN4 (contactin-4) codes for a cell-adhesion molecule gene that has recently been linked to both ASD and AN. 

Objectives:  To investigate on how CNTN4-deficiency may modulate brain development and behavior, we used a Cntn4 gene knockout mouse model to determine how CNTN4 protein contributes to cortical development and behavior. The approach permits empirical evaluation of how variation in CNTN4 may act to modulate risk and presentation in patients with deletion who have classic autism. We have begun to perform behavior analysis and a morphological characterization using mouse model.

Methods:  We assessed a wide variety of health measures, behaviors and cognitive capacities in Cntn4 KO, heterozygous and wild type mice.  In addition, Nissl and Golgi stainings of cortical neurons were analyzed for morphological analysis and reconstruction of dendritic arbors by manual tracing (Neuro Lucida software).

Results:  Our behavioral studies have shown that Cntn4 KO and heterozygous mice made significantly more errors before reaching the criterion for intra-dimensional reversal learning (affective set-shifting) compared to wild type mice (p < 0.05; Student t-test). The mice also needed significantly more trials to complete this sub-task (p < 0.05; Student t-test). In contrast, no effect was found on odor detection or extra-dimensional (attentional) set-shifting. Moreover, no genotype effects were detected in the longitudinal assessment of health measures and other behavioral domains. Interestingly, brain morphology analyses revealed a significant reduction of cortical layer thickness in the motor cortex (p < 0.05; Student t-test), but not in non-frontal areas including somatosensory cortex and visual cortex. 

Conclusions:  Reversal learning is considered a core component of cognitive rigidity, a behavioral domain affected in both ASD and AN. Our behavioral and pathological results in Cntn4 KO mice revealed a link between frontal cortical mechanisms and cognitive rigidity behavior. Together, these findings suggest that this mouse model is highly suitable to examine neurobiological underpinnings of cognitive rigidity in neurodevelopmental disorders. Ultimately, this approach may lead to the development of therapeutic strategies with cross-diagnostic relevance

See more of: Animal Models
See more of: Animal Models