Cadherins and neuropsychiatric disorders

Review

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Abstract

Cadherins mediate cell-cell adhesion but are also involved in intracellular signaling pathways associated with neuropsychiatric disease. 

Most of the ~100 cadherins that are expressed in the brain exhibit characteristic spatiotemporal expression profiles. 

Cadherins have been shown to regulate neural tube regionalization, neuronal migration, gray matter differentiation, neural circuit formation, spine morphology, synapse formation and synaptic remodeling. 

The dysfunction of the cadherin-based adhesive system may alter functional connectivity and coherent information processing in the human brain in neuropsychiatric disease. 

Several neuropsychiatric disorders, such as epilepsy/mental retardation, autism, bipolar disease and schizophrenia, have been associated with cadherins, mostly by genome-wide association studies.

 For example, CDH15 and PCDH19 are associated with cognitive impairment; CDH5, CDH8, CDH9, CDH10, CDH13, CDH15, PCDH10, PCDH19 and PCDHb4 with autism; CDH7, CDH12, CDH18, PCDH12 and FAT with bipolar disease and schizophrenia; and CDH11, CDH12 and CDH13 with methamphetamine and alcohol dependency. 

To date, disease-causing mutations are established for PCDH19 in patients with epilepsy, cognitive impairment and/or autistic features. 

In conclusion, genes encoding members of the cadherin superfamily are of special interest in the pathogenesis of neuropsychiatric disease because cadherins play a pivotal role in the development of the neural circuitry as well as in mature synaptic function.

Keywords

• Brain development;
• Neural circuits;
• Synaptic function;
• Cadherin;
• Catenin;
• Wnts;
• GSK3;
• Lithium;
• Disc1;
• Genetic Linkage;
• Genome-wide association studies;
• Autism;
• Schizophrenia;
• Bipolar Disorders;
• Epilepsy;
• Cognitive Impairment;
• Addiction;
• Alcoholism

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Figures from this article:

Fig. 1. Cadherin expression in limbic structures of the mouse forebrain. The representative examples displayed in this figure serve to illustrate the complexity of (proto-)cadherin expression patterns in different brain regions. Note the intricate region-specific and layer-specific expression profiles that are partially complementary for specific (proto-)cadherin pairs. The pseudocolor-coded overlays (B, D, F) represent in situ hybridization results for pairs of (proto-)cadherins. Frontal sections (A, B, E, F) and horizontal sections (C, D) were hybridized in situ with specific cRNA probes for Pcdh8/Pcdh19 (B), Pcdh17/Pcdh19 (D), and Pcdh10/Cdh4 (F), according to a previously published protocol (Hertel and Redies, 2011). For neuroanatomical orientation, a Nissl (Thio) stain of an adjacent section is displayed in the left panels (A, C, E). A, B. Pcdh8 and Pcdh19 expression in cingulated cortex shows a layer-specific, complementary expression profile in cingulate cortex (Cg) and motor cortex (M). Pcdh8 is restricted to layer III and Pcdh19 is localized in layers II, IV and V of cingulate cortex. The dashed line in B outlines the cortical surface. Data are from the study by Hertel et al. (Hertel and Redies, 2011). C, D. Pcdh19 shows signal in all the three fields of the Ammon's horn (CA1–CA3) in the hippocampal region, whereas Pcdh17 is expressed in a gradient-like manner. Note also the complementary expression in specific layers of the medial entorhinal cortex (MEnt). The arrowheads in C and D designate the border between neocortex and entorhinal cortex (Gudrun Stoya, Nicole Hertel, unpublished data, see also Kim et al., 2011). E, F. Pcdh10 expression in the amygdala is restricted to the deep nuclei, while Cdh4 shows signal in nearly all other parts of the amygdala (Hertel. et al., 2012). The asterisks in C, E and F indicate artefacts. Other abbreviations: I–VI, cortical layers I-VI; ASTr, amygdalostriatal transition area; BLA, anterior part of the basolateral amygdaloid nucleus; BLP, posterior part of the basolateral amygdaloid nucleus; BM, basomedial amygdaloid nucleus; cc, corpus callosum; GD, dentate gyrus; HF, hippocampal fissure; Hil, hilus of the dentate gyrus; LaD, dorsal part of the lateral amygdaloid nucleus; LaVL, ventrolateral part of the lateral amygdaloid nucleus; Me, medial amygdaloid nucleus; PaS, parasubiculum; Pir, piriform cortex; PRh, perirhinal cortex; PrS, presubiculum; sub, subiculum. Scale bars: 250 µm in A (applies to A, B); 500 µm in C (applies to C, D); and 250 µm in E (applies to E, F).

Fig. 2. Schematic diagram of the intracellular signaling pathways related to adhesive functions of cadherins and other molecules associated with neuropsychiatric disease (Wnts, DISC1, GSK3, β-catenin, reelin, lithium, etc.).

 Authors

• Christoph Redies^{a, ,} ,
• Nicole Hertel^a, ,
• Christian A. Hübner^b,

• ^a Institute of Anatomy I, Teichgraben 7, Jena University School of Medicine, Jena University Hospital,D-07740 Jena, Germany
• ^b Institute of Human Genetics, Kollegiengasse 10, Jena University School of Medicine, Jena University Hospital, Jena, Germany

Corresponding author. Fax: +49 3641 938512.

Fuente:  Brain Research