Structural abnormalities in the primary somatosensory cortex and a normal behavioral profile in Contactin-5 deficient mice.

Contactin-5 (Cntn5) is an immunoglobulin cell adhesion molecule that is exclusively expressed in the central nervous system. In view of its association with neurodevelopmental disorders, particularly autism spectrum disorder (ASD), this study focused on Cntn5-positive areas in the forebrain and aimed to explore the morphological and behavioral phenotypes of the Cntn5 null mutant (Cntn5-/-) mouse in relation to these areas and ASD symptomatology. A newly generated antibody enabled us to elaborately describe the spatial expression pattern of Cntn5 in P7 wild type (Cntn5+/+) mice. The Cntn5 expression pattern included strong expression in the cerebral cortex, hippocampus and mammillary bodies in addition to described previously brain nuclei of the auditory pathway and the dorsal thalamus. Thinning of the primary somatosensory (S1) cortex was found in Cntn5-/- mice and ascribed to a misplacement of Cntn5-ablated cells. This phenotype was accompanied by a reduction in the barrel/septa ratio of the S1 barrel field. The structure and morphology of the hippocampus was intact in Cntn5-/- mice. A set of behavioral experiments including social, exploratory and repetitive behaviors showed that these were unaffected in Cntn5-/- mice. Taken together, these data demonstrate a selective role of Cntn5 in development of the cerebral cortex without overt behavioral phenotypes.

Anatomy and Cell Biology of Autism Spectrum Disorder: Lessons from Human Genetics.

Until recently autism spectrum disorder (ASD) was regarded as a neurodevelopmental condition with unknown causes and pathogenesis. In the footsteps of the revolution of genome technologies and genetics, and with its high degree of heritability, ASD became the first neuropsychiatric disorder for which clues towards molecular and cellular pathogenesis were uncovered by genetic identification of susceptibility genes. Currently several hundreds of risk genes have been assigned, with a recurrence below 1% in the ASD population. The multitude and diversity of known ASD genes has extended the clinical notion that ASD comprises very heterogeneous conditions ranging from severe intellectual disabilities to mild high-functioning forms. The results of genetics have allowed to pinpoint a limited number of cellular and molecular processes likely involved in ASD including protein synthesis, signal transduction, transcription/chromatin remodelling and synaptic function all playing an essential role in the regulation of synaptic homeostasis during brain development. In this context, we highlight the role of protein synthesis as a key process in ASD pathogenesis as it might be central in synaptic deregulation and a potential target for intervention. These current insights should lead to a rational design of interventions in molecular and cellular pathways of ASD pathogenesis that may be applied to affected individuals in the future.

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.

Neurobiology of autism gene products: towards pathogenesis and drug targets.

RATIONALE: The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets. OBJECTIVE: The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms. METHOD: Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions. RESULTS: The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity. CONCLUSIONS: ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.

Contactins in the neurobiology of autism.

Autism is a disease of brain plasticity. Inspiring work of Willem Hendrik Gispen on neuronal plasticity has stimulated us to investigate gene defects in autism and the consequences for brain development. The central process in the pathogenesis of autism is local dendritic mRNA translation which is dependent on axodendritic communication. Hence, most autism-related gene products (i) are part of the protein synthesis machinery itself, (ii) are components of the mTOR signal transduction pathway, or (iii) shape synaptic activity and plasticity. Accordingly, prototype drugs have been recognized that interfere with these pathways. The contactin (CNTN) family of Ig cell adhesion molecules (IgCAMs) harbours at least three members that have genetically been implicated in autism: CNTN4, CNTN5, and CNTN6. In this chapter we review the genetic and neurobiological data underpinning their role in normal and abnormal development of brain systems, and the consequences for behavior. Although data on each of these CNTNs are far from complete, we tentatively conclude that these three contactins play roles in brain development in a critical phase of establishing brain systems and their plasticity. They modulate neuronal activities, such as neurite outgrowth, synaptogenesis, survival, guidance of projections and terminal branching of axons in forming neural circuits. Current research on these CNTNs concentrate on the neurobiological mechanism of their developmental functions. A future task will be to establish if proposed pharmacological strategies to counteract ASD-related symptomes can also be applied to reversal of phenotypes caused by genetic defects in these CNTN genes.