A Model for the Involvement of Neural Cell Adhesion Molecules in Stress-Related Mood Disorders

Abstract

Critical interactions between genetic and environmental factors – among which stress is one of the most potent non-genomic factors – are involved in the development of mood disorders. Intensive work during the past decade has led to the proposal of the network hypothesis of depression [Castren E: Nat Rev Neurosci 2005;6:241–246]. In contrast to the earlier chemical hypothesis of depression that emphasized neurochemical imbalance as the cause of depression, the network hypothesis proposes that problems in information processing within relevant neural networks might underlie mood disorders. Clinical and preclinical evidence supporting this hypothesis are mainly based on observations from depressed patients and animal stress models indicating atrophy (with basic research pointing at structural remodeling and decreased neurogenesis as underlying mechanisms) and malfunctioning of the hippocampus and prefrontal cortex, as well as the ability of antidepressant treatments to have the opposite effects. A great research effort is devoted to identify the molecular mechanisms that are responsible for the network effects of depression and antidepressant actions, with a great deal of evidence pointing at a key role of neurotrophins (notably the brain-derived neurotrophic factor) and other growth factors. In this review, we present evidence that implicates alterations in the levels of the neural cell adhesion molecules of the immunoglobulin superfamily, NCAM and L1, among the mechanisms contributing to stress-related mood disorders and, potentially, in antidepressant action.

Genetic Deletion of Lsamp Causes Exaggerated Behavioral Activation in Novel Environments

“…There was no main effect of sex on the y-maze measurements, so data were combined across sex for the analyses. There was a main effect of genotype on y-maze measurements (F (4,49) =17.70, p < 0.0001). As expected, Lsamp −/− mice were hyperactive during the 8-minute exposure to the novel y-maze, as measured by a significant increase (F (1,52) =53.43, p < 0.0001) in the total number of arm entries (Fig.…”

“…Lsamp is expressed robustly throughout the limbic circuitry responsible for mediating an animal's behavioral response to novelty (including circuitry that mediates fear, stress and exploratory behavior). Alterations in emotional regulation can be due both to direct changes in neurotransmitter function [16,22,50,53] and to alterations of synaptic connectivity [49,53]. Because Lsamp is expressed from the time that neurons become postmitotic prenatally and throughout the life of the animal, conditional and reversible manipulation of gene expression will be necessary to determine whether the behavioral dysfunction exhibited by the Lsamp −/− mice are due to differential development of limbic circuitry, direct modulation of mature synaptic function in the adult, or even both.…”

The interplay of conditional NCAM-knockout and chronic unpredictable stress leads to increased aggression in mice

“…The expression levels of NCAM and its binding properties are crucial for neural remodeling and synaptic function. Disturbances in NCAM expression and dysregulation of NCAM signaling have been linked to various psychiatric disorders, such as depression, bipolar disorder and schizophrenia in humans (Brennaman & Maness, 2010;Chekhonin et al, 2008;Cunningham et al, 1987;Poltorak et al, 1995;Vawter et al, 1999; for review, see Sandi & Bisaz, 2007), as well as with changes in emotional and social behaviors in animal models (Conboy et al, 2010;Stork et al, 1999Stork et al, , 2000. Of specific interest is pathological aggression, a key symptom in mental disorders (such as antisocial personality disorder and borderline personality disorder) which is also characteristic of many other psychiatric diseases, such as mood disorders and schizophrenia (Haller & Kruk, 2006;Neumann et al, 2010;Veenema & Neumann, 2007).…”

Learning under stress: A role for the neural cell adhesion molecule NCAM

“…Increasing evidence also points out that inappropriate stress responses and/or control might be associated with the development of physiological alterations and neuropsychiatric disorders (de Kloet, Joels, & Holsboer, 2005;Heim & Nemeroff, 1999;Mazure, Kincare, & Schaffer, 1995;McEwen, 2005;Sandi & Bisaz, 2007;Wiedenmayer, 2004).…”