Cntn4, encoding the contactin 4 protein, is a crucial synaptic adhesion protein belonging to the contactin superfamily. It has been genetically linked to various neuropsychiatric disorders such as autism spectrum disorder (ASD), anorexia nervosa (AN), Alzheimer's disease (AD), and schizophrenia (SZ) [3,4]. Mouse models have been instrumental in studying its functions.

Cntn4 -deficient mouse models have shown its significance in multiple neural processes. In the hippocampus, Cntn4 modulates synaptic plasticity and is involved in fear memory, with abnormal dendritic arborization and spines in hippocampal CA1 neurons in knockout mice [3]. In the motor cortex of Cntn4 -/- mice, cortical thickness is reduced, and it impacts neuron morphology and spine density [1]. Knockout human cells for CNTN4 and amyloid-precursor protein (APP) revealed that CNTN4 binds and interacts with APP to control neural elongation [1]. In cortical neurons, disruption of Cntn4 decreases excitatory synapses, reduces neural activity, and impairs dendritic spine formation, with autism-related variants lacking the ability to regulate spine density and neural activity [2].

In conclusion, Cntn4 is essential for neural development, influencing processes like axon guidance, synaptic plasticity, dendritic spine formation, and neural elongation. Mouse knockout models have been vital in revealing its role in neuropsychiatric disorders, highlighting its potential as a key target for understanding and treating these conditions.

References:

1. Bamford, Rosemary A, Zuko, Amila, Eve, Madeline, Burbach, J Peter H, Oguro-Ando, Asami. 2024. CNTN4 modulates neural elongation through interplay with APP. In Open biology, 14, 240018. doi:10.1098/rsob.240018. https://pubmed.ncbi.nlm.nih.gov/38745463/

2. Zhao, Rongjuan, Zhu, Tengfei, Liu, Qiong, Qiu, Zilong, Hu, Zhengmao. . The autism risk gene CNTN4 modulates dendritic spine formation. In Human molecular genetics, 31, 207-218. doi:10.1093/hmg/ddab233. https://pubmed.ncbi.nlm.nih.gov/34415325/

3. Oguro-Ando, Asami, Bamford, Rosemary A, Sital, Wiedjai, Burbach, J Peter H, Kas, Martien J. 2021. Cntn4, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior. In Translational psychiatry, 11, 106. doi:10.1038/s41398-021-01223-y. https://pubmed.ncbi.nlm.nih.gov/33542194/

4. Zhang, Stephanie Q, Fleischer, Julie, Al-Kateb, Hussam, Amarillo, Ina, Shinawi, Marwan. 2019. Intragenic CNTN4 copy number variants associated with a spectrum of neurobehavioral phenotypes. In European journal of medical genetics, 63, 103736. doi:10.1016/j.ejmg.2019.103736. https://pubmed.ncbi.nlm.nih.gov/31422286/