<i>Cntn4</i>, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior

Neurodevelopmental and neuropsychiatric disorders, such as autism spectrum disorders (ASD), anorexia nervosa (AN), Alzheimer’s disease (AD), and schizophrenia (SZ), are heterogeneous brain disorders with unknown etiology. Genome wide studies have revealed a wide variety of risk genes for these disorders, indicating a biological link between genetic signaling pathways and brain pathology. A unique risk gene is Contactin 4 (Cntn4), an Ig cell adhesion molecule (IgCAM) gene, which has been associated with several neuropsychiatric disorders including ASD, AN, AD, and SZ. Here, we investigated the Cntn4 gene knockout (KO) mouse model to determine whether memory dysfunction and altered brain plasticity, common neuropsychiatric symptoms, are affected by Cntn4 genetic disruption. For that purpose, we tested if Cntn4 genetic disruption affects CA1 synaptic transmission and the ability to induce LTP in hippocampal slices. Stimulation in CA1 striatum radiatum significantly decreased synaptic potentiation in slices of Cntn4 KO mice. Neuroanatomical analyses showed abnormal dendritic arborization and spines of hippocampal CA1 neurons. Short- and long-term recognition memory, spatial memory, and fear conditioning responses were also assessed. These behavioral studies showed increased contextual fear conditioning in heterozygous and homozygous KO mice, quantified by a gene-dose dependent increase in freezing response. In comparison to wild-type mice, Cntn4-deficient animals froze significantly longer and groomed more, indicative of increased stress responsiveness under these test conditions. Our electrophysiological, neuro-anatomical, and behavioral results in Cntn4 KO mice suggest that Cntn4 has important functions related to fear memory possibly in association with the neuronal morphological and synaptic plasticity changes in hippocampus CA1 neurons

CNTN4 modulates neural elongation through interplay with APP

The neuronal cell adhesion molecule contactin-4 (CNTN4) is genetically associated with autism spectrum disorder (ASD) and other psychiatric disorders. Cntn4-deficient mouse models have previously shown that CNTN4 plays important roles in axon guidance and synaptic plasticity in the hippocampus. However, the pathogenesis and functional role of CNTN4 in the cortex has not yet been investigated. Our study found a reduction in cortical thickness in the motor cortex of Cntn4 -/- mice, but cortical cell migration and differentiation were unaffected. Significant morphological changes were observed in neurons in the M1 region of the motor cortex, indicating that CNTN4 is also involved in the morphology and spine density of neurons in the motor cortex. Furthermore, mass spectrometry analysis identified an interaction partner for CNTN4, confirming an interaction between CNTN4 and amyloid-precursor protein (APP). Knockout human cells for CNTN4 and/or APP revealed a relationship between CNTN4 and APP. This study demonstrates that CNTN4 contributes to cortical development and that binding and interplay with APP controls neural elongation. This is an important finding for understanding the physiological function of APP, a key protein for Alzheimer's disease. The binding between CNTN4 and APP, which is involved in neurodevelopment, is essential for healthy nerve outgrowth

Immunoprecipation Assay to Quantify the Amount of tRNAs associated with Their Interacting Proteins in Tissue and Cell Culture

Transfer RNAs (tRNAs) are highly abundant species and, along their biosynthetic and functional path, they establish interactions with a plethora of proteins. The high number of nucleobase modifications in tRNAs renders conventional RNA quantification approaches unsuitable to study protein-tRNA interactions and their associated functional roles in the cell. We present an immunoprecipitation-based approach to quantify tRNA bound to its interacting protein partner(s). The tRNA-protein complexes are immunoprecipitated from cells or tissues and tRNAs are identified by northern blot and quantified by tRNA-specific fluorescent labeling. The tRNA interacting protein is quantified by an automated western blot and the tRNA amount is presented per unit of the interacting protein. We tested the approach to quantify tRNA(Gly) associated with mutant glycyl-tRNA-synthetase implicated in Charcot-Marie-Tooth disease. This simple and versatile protocol can be easily adapted to any other tRNA binding proteins. Graphic abstract: [Image: see text

A current view on contactin-4, -5, and -6 : Implications in neurodevelopmental disorders

Contactins (Cntns) are a six-member subgroup of the immunoglobulin cell adhesion molecule superfamily (IgCAMs) with pronounced brain expression and function. Recent genetic studies of neuropsychiatric disorders have pinpointed contactin-4 (CNTN4), contactin-5 (CNTN5) and contactin-6 (CNTN6) as candidate genes in neurodevelopmental disorders, particularly in autism spectrum disorders (ASDs), but also in intellectual disability, schizophrenia (SCZ), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD), alcohol use disorder (AUD) and anorexia nervosa (AN). This suggests that they have important functions during neurodevelopment. This suggestion is supported by data showing that neurite outgrowth, cell survival and neural circuit formation can be affected by disruption of these genes. Here, we review the current genetic data about their involvement in neuropsychiatric disorders and explore studies on how null mutations affect mouse behavior. Finally, we highlight to role of protein–protein interactions in the potential mechanism of action of Cntn4, -5 and -6 and emphasize that complexes with other membrane proteins may play a role in neuronal developmental functions

tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

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tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase.

[Figure: see text]

Association of Cell Adhesion Molecules Contactin-6 and Latrophilin-1 Regulates Neuronal Apoptosis

In view of important neurobiological functions of the cell adhesion molecule contactin-6 (Cntn6) that have emerged from studies on null-mutant mice and autism spectrum disorders patients, we set out to examine pathways underlying functions of Cntn6 using a proteomics approach. We identified the cell adhesion GPCR latrophilin-1 (Lphn1, a.k.a. CIRL1/CL, ADGRL1) as a binding partner for Cntn6 forming together a heteromeric cis-complex. Lphn1 expression in cultured neurons caused reduction in neurite outgrowth and increase in apoptosis, which was rescued by coexpression of Cntn6. In cultured neurons derived from Cntn6(-/-) mice, Lphn1 knockdown reduced apoptosis, suggesting that the observed apoptosis was Lphn1-dependent. In line with these data, the number of apoptotic cells was increased in the cortex of Cntn6(-/-) mice compared to wild-type littermate controls. These results show that Cntn6 can modulate the activity of Lphn1 by direct binding and suggests that Cntn6 may prevent apoptosis thereby impinging on neurodevelopment