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

Fax +41 61 306 12 34E-Mail [email protected]

Signaling Mechanisms Underlying Neuroendocrine Function

Neuroendocrinology 2007;85:158–176 DOI: 10.1159/000101535

A Model for the Involvement ofNeural Cell Adhesion Molecules inStress-Related Mood Disorders

Carmen Sandi Reto Bisaz

Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne , Switzerland

and malfunctioning of the hippocampus and prefrontal cor-tex, 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 ac-tions, with a great deal of evidence pointing at a key role of neurotrophins (notably the brain-derived neurotrophic fac-tor) and other growth factors. In this review, we present evi-dence that implicates alterations in the levels of the neural cell adhesion molecules of the immunoglobulin superfami-ly, NCAM and L1, among the mechanisms contributing to stress-related mood disorders and, potentially, in antide-pressant action. Copyright © 2007 S. Karger AG, Basel

Introduction

Stress, particularly when uncontrollable, excessive and/or prolonged, can produce a myriad of emotional and cognitive alterations. In some individuals, stress can eventually trigger or exacerbate mood disorders, among which depression and bipolar disorders appear to be par-ticularly linked to aversive life experiences [1] . Chronic stress procedures are currently widely used in experi-mental animals (mainly rodents and a few primate stud-ies) to model depression [2–5] .

Despite great interest to understand the neurobiologi-cal alterations responsible both for depression and for the

Key Words Depression � Network hypothesis of depression � Neural cell adhesion molecules � L1 � NCAM � PSA-NCAM � Neurocircuitry structure and function � Neurotrophins and growth factors � Stress-related mood disorders � Antidepressant � Neurogenesis � BDNF � Structural remodeling � Chronic stress

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 [Cas-tren 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 support-ing this hypothesis are mainly based on observations from depressed patients and animal stress models indicating at-rophy (with basic research pointing at structural remodeling and decreased neurogenesis as underlying mechanisms)

Received: January 17, 2007 Accepted after revision: February 2, 2007 Published online: April 3, 2007

Carmen Sandi Brain Mind Institute, AAB, Station 15, EPFL CH–1015 Lausanne (Switzerland) Tel. +41 21 693 9534, Fax +41 21 693 9636 E-Mail [email protected]

© 2007 S. Karger AG, Basel0028–3835/07/0853–0158$23.50/0

Accessible online at:www.karger.com/nen

Presented at the Sixth International Congress of Neuroendocrinol-ogy, June 19–22, 2006, Pittsburgh, Pa., USA.

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http://dx.doi.org/10.1159%2F000101535

Neural Cell Adhesion Molecules and Depression

Neuroendocrinology 2007;85:158–176 159

effective recovery from depression, the mechanisms un-derlying mood disorders are still not well understood [6] . After much research devoted to the chemical hypothesis of depression (that hypothesizes alterations in the brain neurotransmitter balance as the main cause of the dis-ease), a prevailing view these days is that mood disorders are associated with impaired information processing in critical neural networks [7, 8] . This new view, termed the ‘network hypothesis’, in addition to postulating that per-turbed neuronal communication underlies depression, presumes that antidepressants act by improving the pro-cessing of information in the defective circuits [7] . It should be noted, though, that the chemical and network hypotheses should not be regarded as mutually exclusive, since changes in neurotransmitter balance would most probably result in circuit modifications, and vice versa.

In this review, we will start by briefly presenting the main lines of evidence supporting the network hypoth-esis of depression, followed by a brief discussion on the neurotrophic hypothesis developed to account for the mechanisms underlying the structural and functional changes induced by stress and antidepressants. Recent clinical and preclinical work has highlighted the neural cell adhesion molecules of the immunoglobulin super-family, NCAM and L1, as particularly susceptible to showing alterations in stress-related disorders and de-pression. Our main goal is, then, to discuss evidence to implement these molecules as new players among the mechanisms contributing to mood disorders within the framework of the network hypothesis of depression. We will examine the functional consequences of interfering with either their content or function in relevant brain cir-cuits on neurobiological and behavioral ‘readouts’ of de-pression. Finally, we will propose a testable model about the contribution of NCAM and its polysialylated form (PSA-NCAM) and L1 in stress-related mood disorders.

Clinical and Preclinical Evidence for the Network Hypothesis of Depression

Clinical Evidence Evidence supporting the network hypothesis of de-

pression is still scarce, since there are still important methodological limitations to measuring changes in neu-ronal networks in vivo. However, indirect evidence sup-ports the existence of important morphological changes in the depressed human brain. At the macro-anatomical level, human studies have shown reductions in the volume of brain areas that play a key role in emotional and cogni-

tive integration (such as the hippocampus and prefrontal cortex) in patients with depression [9–13] . Moreover, functional neuroimaging and postmortem studies in hu-mans with mood disorders have revealed a limbic-cortical dysfunction, including alterations in areas of prefrontal cortex (PFC), hippocampus, and amygdala [14–20] . In de-pressed patients, marked reductions in cortical volume and neuronal and glial density have been reported [21–23] , with a corresponding reduction in blood flow [24] . Evidence indicates that, to a certain extent, structural shrinkage can be reversed by antidepressant treatment [13, 25] . Interestingly, some of these alterations were also successfully restored by antidepressant therapy in a pri-mate model of stress-induced depression [26] .

Which cellular mechanisms may underlie the reduc-tions in hippocampal and PFC volume reported to occur in depressed patients? Mounting evidence from animal stress studies points at two potential mechanisms: (i) neuronal structural remodeling, and (ii) reduced neuro-genesis. In the next two subsections, we will review such evidence, along with recent work indicating that antide-pressants can also exert their effects by affecting these cellular mechanisms.

Stress and Structural Remodeling Initially, the hippocampus was the brain region that re-

ceived closer attention due to the many reports indicating impairing effects of chronic stress in hippocampus-depen-dent memory tasks [27] . However, intensive work is now providing evidence for a more integral impact of chronic stress throughout the brain, with major changes having also being reported for the PFC and the amygdala. Al-though changes in dendritic branching and synaptogene-sis occurring in the amygdala are plausible candidates to participate in stress-induced mood alterations [28, 29] , we will focus here on changes occurring at the level of the hip-pocampus and the PFC, given that: (i) alterations in amyg-dala structure and function have not yet been implement-ed in the current ideas sustaining the network hypothesis of depression [7] ; (ii) no data has yet been provided, to our knowledge, about the impact of antidepressants on amyg-dala structure and function, and (iii) there is very limited knowledge [30] about the effect of stress on the expression of cell adhesion molecules in this brain region.

Hippocampus. The hippocampus is well known for its crucial role in memory processes [31, 32] . Hippocampus-dependent tasks are generally affected by both acute and chronic stress manipulations [33–36] . In humans, neuro-imaging studies have reported hippocampal atrophy in association with stress- and glucocorticoid-related cog-

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Neuroendocrinology 2007;85:158–176160

nitive and neuropsychiatric alterations [19, 37, 38] , in-cluding depression [9–11, 39–41] .

In rodents, a prominent and often replicated effect is a dendritic atrophy in apical dendrites from CA3 pyramidal neurons [42, 43] ( fig. 1 ). This reduced dendritic branching has been associated with (i) a reduction in synaptic den-sity of excitatory glutamatergic synapses [44, 45] ; (ii) a shrinkage of the volume of the complex dendritic spines termed dendritic excrescences, that are located on the

proximal apical dendrite and soma of CA3 pyramidal cells and which serve as postsynaptic targets for the mossy fiber synaptic inputs [46] , and (iii) a rearrangement of synaptic vesicles and mitochondria in the afferent mossy fiber ter-minals [47] . On its turn, evidence for synaptic remodel-ing – in terms of changes in synaptic features – has also been reported for the hippocampal CA1 region [44, 48] .

Prefrontal Cortex. The PFC, and more precisely its me-dial part (mPFC), plays key roles in higher cognitive pro-

Fig. 1. Physiological stress response and its long-term conse-quences on neuronal structure in the hippocampus. a When an organism is exposed to stress, alterations in hippocampus and amygdala activity lead to the stimulation of the sympathetic ner-vous system and the hypothalamic-pituitary-adrenocortical (HPA) axis. Activation of the HPA axis results in the production of two peptides, corticotrophin-releasing hormone (CRH) and vasopressin (AVP) in the paraventricular nucleus of the hypo-thalamus, which are then released into the hypophyseal portal blood system. Both peptides thereafter activate the anterior pitu-itary to secrete adrenocorticotropic hormone (ACTH) into the bloodstream, which stimulates the adrenal cortex to produce and release glucocorticoids (cortisol in humans, corticosterone in ro-

dents). Crucial for health and survival of the organism is an ap-propriate control of the HPA axis, which is fulfilled by negative feedback mechanisms. Glucocorticoids (through mineralocorti-coid and glucocorticoid receptors) signal back to the anterior pi-tuitary, the hypothalamus and the hippocampus, whereby pro-duction and secretion of hormones are suppressed. b When an organism is exposed to prolonged stress, or if an appropriate con-trol of the HPA axis is not possible, elevated glucocorticoid levels in the blood flow over long time periods result. Such long-lasting elevated glucocorticoid concentrations lead to a reduction in the number and length of apical dendrites in the CA3 region (den-dritic atrophy), as well as to inhibited neurogenesis in the dentate gyrus of the hippocampus.

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cesses (including executive function, working memory, attention), as well as in the integration of cognitive and emotionally relevant information [49–51] . It should be noted that the mPFC contains high levels of glucocorti-coid receptors [52, 53] and is involved in the regulation of stress-induced hypothalamic-pituitary-adrenal (HPA) activity [54] . As noted above, clinical evidence highlights the mPFC as an area that experiences marked alterations in a wide variety of neuropsychiatric disorders [15, 55] , including depression [12, 13] .

There is also substantial evidence from rodent studies for stress-induced dendritic shrinkage in the PFC. In par-ticular, major neuronal remodeling was described to oc-cur in layer II/III of the mPFC as a consequence of re-peated exposure to chronic stress or repeated glucocorti-coid treatment. The major described changes in this area are: (i) a dendritic atrophy, including both decrease of to-tal length [56, 57] and number [56] of apical dendrites from pyramidal neurons, and (ii) a decrease (approxi-mately one-third of all axospinous synapses on apical dendrites of pyramidal neurons are lost) in apical den-dritic spine density [58] . Interestingly, glucocorticoids seem to be major players in the remodeling induced by stress in the mPFC [59, 60] .

Antidepressant Effects . Treatment with the atypical (modified tricyclic) antidepressant tianeptine was shown to reverse dendritic atrophy induced by chronic stress in CA3 pyramidal neurons [42, 43, 61–63] in rats. Moreover, antidepressants were also reported to facilitate axonal and dendritic sprouting [64, 65] . These findings suggest that antidepressants can have a major impact on neuronal remodeling, providing the basis for relevant circuits to be reorganized in the course of recovery from depression.

Stress, Antidepressants, and Hippocampal Neurogenesis Stress and high glucocorticoid levels can suppress

neurogenesis in the dentate gyrus [66, 67] . A large num-ber of stress models have been shown to decrease hippo-campal neurogenesis in rodents [68, 69] ( fig. 1 ). Likewise, reduced neurogenesis has also been reported in tree shrews exposed to psychosocial stress [26] . Glucocorti-coid effects on neurogenesis are mediated, by activation of the glucocorticoid receptor (GR) [70] and the N -meth-yl- D -aspartate (NMDA) receptor [71] .

As opposed to stress, antidepressant treatment has been repeatedly found to promote neurogenesis. Several rodent studies have documented this phenomenon fol-lowing chronic antidepressant treatment in, otherwise, undisturbed animals [23, 68, 72–75] . Moreover, antide-

pressant drugs were also described to revert decreased neurogenesis induced by chronic stress both in rodents and tree shrews [26, 76] .

The functional importance of the link between anti-depressants and neurogenesis was supported by an ele-gant study in mice reported by Santarelli et al. [75] . By using genetic and radiological methods, these authors showed that disrupting antidepressant-induced neuro-genesis blocks behavioral responses of antidepressants. The authors suggested that the behavioral effects of chronic antidepressants might be mediated by the stimu-lation of neurogenesis in the hippocampus, a possibility that has caused a major impact in the area of neurophar-macology [77] .

The fact that the clinical effects of antidepressants develop over the course of around 3 weeks fits with the time course that takes new neurons to mature and get integrated in functional circuits [78] further support the network hypothesis of depression. In parallel with such a hypothesis, a neurogenic hypothesis of depression and antidepressant action [68] has also been suggested. How-ever, acceptance of these hypotheses is still pending more definitive proofs from in vivo studies indicating that these are, indeed, the mechanisms responsible for depression and antidepressant-related mood changes [7] .

Stress and Cell Death Although most work is currently concentrating in

the deleterious effects of stress in neurogenesis, another way whereby stress can affect hippocampal cell number is by compromising cell survival. An intensive line of research suggested that stress and excessive glucocorti-coids can have such effects and eventually lead to overt neuronal loss by exacerbating the neurotoxicity that is induced by other hippocampal insults [79] . A recent study presented evidence suggesting that chronic (5 weeks) psychosocial stress in tree shrews might lead to decreased number of GABAergic interneurons in all hippocampal areas except in CA1 [80] . Interestingly, antidepressant treatment, notably by NK1R (a novel neurokinin 1 receptor antagonist), and partially by the selective serotonin reuptake inhibitor (SSRI) fluoxetine prevented the stress-induced reduction of the number of interneurons, when administered from the second week of stress [80] .

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Molecular Mechanisms Implicated in the Network Hypothesis of Depression – the Role of Neurotrophins and Growth Factors

There is great interest to identify the key molecular mechanisms that mediate the effects of stress and antide-pressants in structural remodeling and neurogenesis. Ex-tensive work during the past two decades has highlighted a wide variety of molecules – ranging from excitatory amino acids to cell adhesion molecules – as critically in-volved in the deleterious effects of chronic stress [27, 81] and antidepressant [82] actions.

Among them, much attention has been focused on neurotrophic factors, and especially to the brain-derived neurotrophic factor (BDNF). The central role hypothe-sized for this molecule in stress-related mood disorders [83] is supported by several lines of evidence showing that (i) BDNF expression is decreased by stress and cor-ticosterone administration in limbic structures – notably the hippocampus – that play a prominent role in emotion and cognition [84–87] ; (ii) conversely, treatment with different types of antidepressants consistently blocks most of the behavioral and structural effects of stress as well as enhances BDNF expression in the hippocampus [88–92] ; (iii) BDNF produces antidepressant effects in models of depression [93–95] , and (iv) BDNF stimulates [96] and promotes neurogenesis [23, 83] .

The vascular endothelial growth factor (VEGF) is an-other growth factor whose expression is decreased by stress [97] and upregulated by antidepressants [69] . VEGF facilitation of cell proliferation [98–100] seems to play a coordinated role with BDNF in coordinating different phases of neurogenesis, with the main role of BDNF be-ing on the promotion of cell survival.

Furthermore, hippocampal expression of fibroblast growth factor 2 (FGF2) is also reduced by stress [101, 102] and increased by antidepressant treatment [103] . FGF2 has been proposed as a potential neurogenic mitogen [104–106] . The importance of this growth factor and its receptors in depression has been recently supported by a postmortem gene profiling study showing a profound dysregulation of this family of molecules in depressed pa-tients, which was markedly attenuated in those patients that had received antidepressant treatment [107] .

Among the potential mechanisms mediating the link between growth factors, structural modifications and mood disorders is glycogen synthase kinase 3 � (GSK-3 � ). GSK-3 has been implicated as a critical substrate in growth factor-induced hippocampal structural changes [108] . Interestingly, onset of bipolar disorder has been as-

sociated with BDNF and GSK-3 � genes [109] , and the mood stabilizer lithium chloride has been reported to in-hibit GSK-3 activity [110] .

Given the opposite regulation of these factors by stress and antidepressants, as well as their regulatory roles in structural remodeling and neurogenesis, a prominent view these days is that these neurotrophic factors are in-volved in the pathophysiology and/or treatment of de-pression [7, 68, 83] . More precisely, the hypothesis has been put forward that alterations in the levels or func-tionality of these factors could contribute to either abnor-mal information processing (the network hypothesis of depression) or to recovery from such an abnormal func-tioning [7, 83] . In any case, Duman and Monteggia [83] have emphasized that the key element in both depression and antidepressant actions should be the functioning of relevant neurocircuits.

Clinical and Preclinical Evidence for a Role of the Neural Cell Adhesion Molecules NCAM and L1 in Stress-Related Mood Disorders

In addition to neurotrophins and growth factors, oth-er type of molecules that are also affected by stress and antidepressants might as well play a crucial role in the functioning of relevant neurocircuits involved in the pro-cessing of emotion and cognition. According to evidence discussed below, the neural cell adhesion molecules of the immunoglobulin family, NCAM and L1 (see box 1) can be important players on structural remodeling related to stress and mood disorders. Importantly, these molecules play a key role in neural connectivity and cognition (see box 2), and increasing evidence indicates that they are (i) altered in neuropsychiatric patients, including patients with mood disorders; (ii) markedly affected in animal models of chronic stress, and (iii) altered by antidepres-sant treatments ( table 1 ).

Clinical Evidence

Increased levels of NCAM-immunoreactive proteins (primarily the 120-kDa band) were found in the CSF of patients with mood disorders (notably, bipolar mood dis-order type I and recurrent unipolar major depression) [148] . Such a 120-kDa NCAM band was postulated to derive from CNS cells as a secreted soluble NCAM iso-form. Its increased presence in the CSF of patients with mood disorders suggested the possibility of latent state-

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Box 1. Neural cell adhesion molecules of the immunoglobulin superfamily: NCAM and L1

NCAM and L1 are cell surface macromolecules which belong to the immunoglobulin (Ig) superfamily of cell adhesion mole-cules. They mediate homophilic (NCAM-NCAM or L1-L1) and heterophilic (NCAM-L1) binding, and are known to play key roles in cell-cell interactions. By interacting with tyrosine ki-nases and cytoskeleton components, they can activate specific intracellular signaling pathways and thereby promote neurite extension, axon guidance, cell differentiation, survival and syn-aptogenesis. Interfering with NCAM and L1 function or their ablation in transgenic animals has been shown to impair synap-tic plasticity and memory formation [111–116] (see box 2).

NCAM NCAM is expressed in the vertebrate nervous system as three

main isoforms of different relative molecular weight: NCAM-120, NCAM-140 and NCAM-180. All three isoforms are gener-ated by alternative splicing of the transcript from a single NCAM gene and are further modulated by various posttranslational modifications [117, 118] . The extracellular part of all three main NCAM isoforms consists of five Ig-homology domains and two fibronectin type III-homology domains. Whereas NCAM-120 is attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor, NCAM-140 and NCAM-180 are transmembrane proteins with cytoplasmic domains of different length. It is mainly NCAM-140, but also NCAM-180 which promote neurite outgrowth in migrating growth cones.

One of the most important posttranslational modifications of NCAM is the glycosylation of two asparagine residues in the fifth Ig-homology domain, which consists of long linear � 2,8-linked homopolymers of sialic acid (PSA). Polysialylation of NCAM (PSA-NCAM) decreases NCAM-mediated cell-cell ad-hesion due to steric repulsion of the negatively charged sialic acid residues and their resulting large hydrate volume. PSA-NCAM is widely expressed in the embryonic and early postnatal brain and remains restricted to adult brain areas, which show a high level of structural plasticity, such as the olfactory bulb, the dentate gyrus and the hypothalamus. The addition of PSA to NCAM is facilitated by the two polysialyltransferases, ST8SiaIV/PST and ST8SiaII/STX, whose activity and expression are tem-porally and spatially restricted; STX being mainly expressed in the embryo whereas PST is more prominent in the postnatal brain.

L1 L1 is a member of a subfamily of four mammalian cell surface

glycoproteins. It has an apparent mass of 200 kDa and contains six Ig-homology domains linked to five fibronectin type III-ho-mology domains on the extracellular surface. In mammals, it is expressed throughout the nervous system and in particular at regions of contact between neighboring axons and on growth cones, where it modulates many cellular functions. Mutations in the L1 gene are responsible for several X-linked recessive neuro-logical disorders which also include mental retardation [119, 120] .

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related disturbances in NCAM cellular function, i.e., res-idue from a previous episode, or abnormal NCAM turn-over in the CNS of these patients [148] . Although it re-mains to be established, increased CSF levels of NCAM might indirectly imply reduced expression in central brain areas.

An NCAM dysregulation hypothesis of neuropsychi-atric disorders was presented by Vawter [149] . Enduring dysregulation of NCAM was hypothesized to be related to cognitive impairments, increased lateral ventricle vol-ume, and decreased hippocampal volume observed in schizophrenia and, to a lesser extent, in bipolar disorder.

In a postmortem study, Vawter et al. [143] showed that differently spliced NCAM isoforms are increased in the hippocampus of patients with bipolar disorder compared with those of control subjects. Animal experiments (see box 2) also support this NCAM hypothesis, in that inter-fering with NCAM function results in parallel impair-ments in synaptic plasticity and cognitive function. Giv-en the role of NCAM in synapse stability and plasticity, synaptic dysfunction may be part of the molecular pa-thology of these disorders.

In support for this hypothesis and, in particular, for the link between NCAM and mood disorders is recent evidence in the Japanese population indicating an asso-ciation of NCAM gene polymorphisms with bipolar af-fective disorder [145] . Specifically, three genetic poly-morphisms were found to display significant associations with bipolar disorder. Moreover, the haplotype located in a linkage disequilibrium block was strongly associated with the disorder [145] .

In a postmortem study [150] , the adhesion molecule L1 was found to be increased in the PFC of depressed sub-jects, whereas it was decreased in the parieto-occipital cortex. Interestingly, depressed subjects receiving antide-pressants showed increased L1 expression levels in the parieto-occipital cortex compared to unmediated de-pressed subjects, although no complete reconstitution of normal L1 levels has been ascertained.

Animal Studies of Chronic Stress Chronic stress can markedly affect the expression of

cell adhesion molecules in the hippocampus. Most of the studies to date were performed in rats submitted to dif-ferent stress-induction protocols, and recent evidence in mice seems to confirm the findings.

NCAM . Exposure of rats to chronic stress for 21 days was found to result in reduced NCAM mRNA and pro-tein expression in the hippocampus [151, 152] . Stress spe-cifically reduced NCAM-140 protein expression [153, 154] , while mRNA encoding for the NCAM-180 isoform remained unchanged [152] . Interestingly, animals that showed a particular sensitivity to display cognitive defi-cits following chronic stress experienced a particularly pronounced decrease in hippocampal NCAM-140 ex-pression. Furthermore, a mild (but significant and wide-spread) decrease in NCAM mRNA levels was also ob-served throughout the brain [152] . Glucocorticoids seem to participate in these effects of stress, since chronic treat-ment with corticosterone resulted in decreased NCAM expression in the frontal cortex [135] .

Box 2. Cell adhesion molecules, synaptic plasticity, and cognitive function

Several lines of evidence indicate a critical role for NCAM and L1 in neural connectivity and cognition. Their expression is regulated in learning-related brain areas during memory consolidation [27, 45, 121–123] and interfering with their func-tion either through the administration of antibodies, peptides, or antisense oligonucleotides impaired hippocampal LTP [115, 116, 124] and memory formation [121, 125–127] . Moreover, both synaptic plasticity [114, 128–131] and cognitive processes [114, 130, 132] were also disrupted by genetic deletion of these adhesion molecules. Interestingly, NCAM has also been impli-cated in the stress- and/or glucocorticoid-induced long-term memory enhancement in several animal species, including chicks [133] , mice [134] , and rats [45, 122, 135] .

Likewise, strong plasticity- and memory-promoting prop-erties have been ascribed to PSA-NCAM. Impaired LTP and learning were found as a consequence of enzymatic cleavage of PSA from NCAM through the administration of the enzyme endoneuraminidase-N (endo-N) [123, 136–138] , which is in agreement with reports indicating transient training-induced and memory-related increases in PSA-NCAM expression [27, 45, 139, 140] . Further evidence comes from studies showing impaired LTP and fear learning in mice lacking a functional gene for the polysialyltransferases ST8SiaIV (PST) [141] or ST8Sia-II (STX) [142] , respectively.

Clinical studies add extra support for a key role of these molecules in cognition. Mutations of L1 in humans produce a spectrum of neurologic abnormalities and mental retardation [120] . In addition, increasing evidence relates NCAM with the occurrence of a variety of neuropsychiatric disorders. Thus, NCAM has been found (i) to be altered in an isoform-specific manner in the hippocampus and PFC of schizophrenic pa-tients [143] , who also show abnormal concentrations of a cleaved NCAM isoform [144] ; (ii) to present a possible genetic linkage with bipolar affective disorder [145] , and (iii) to be ex-pressed in increased levels in sera from patients with dementia of the Alzheimer type [146] . Moreover, strong expression of PSA-NCAM has also been described in the hippocampus of Alzheimer’s disease patients [147] .

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Recently, a reduction on NCAM gene expression was also reported in males, but not females, the gender that has been repeatedly shown not to be cognitively affected by chronic stress [155] , from two strains of mice after chronic stress [156] . This effect was observed in parallel with reduced expression of BDNF [156] . Interestingly, acute stress that impairs retrieval of spatial information can also diminish NCAM expression levels in hippocam-pus and PFC [157] .

Of particular interest in the context of the network hypothesis of depression is the finding that early postna-tal stress was also reported to cause a profound reduction of NCAM expression in the hippocampus and cortex when the rats reach adulthood [158] . Given that aversive life experiences represent an important risk factor for the later occurrence of mood disorders [159–161] , dysregula-tion of NCAM expression during development can play a key role in the formation of neural circuits with en-

Table 1. Regulation of cell adhesion molecules by stress, depression, antidepressant treatment, exercise and lesions

Treatment Effect Reference

Stress, hippocampus21 days chronic restrain stress, rats f total NCAM protein and mRNA, Sandi et al., 2001 [151]

d PSA-NCAM,d L1

21 days chronic restrain stress, rats f total NCAM mRNA, Venero et al., 2002 [152] d L1 mRNA

21 days chronic social stress, rats f NCAM-140 protein levels Touyarot et al., 2004 [153]21 days chronic restrain stress, rats f NCAM-140 protein levels Touyarot and Sandi, 2002 [154]

d PSA-NCAM21 days chronic restrain stress, male mice f total NCAM mRNA Alfonso et al., 2006 [156]Early postnatal immobilization, rats f NCAM-140 and NCAM-180 expression Koo et al., 2003 [158]21 days chronic restrain stress, rats d PSA-NCAM Pham et al., 2003 [163]6 weeks chronic restrain stress, rats = PSA-NCAM6 weeks variable unpredictable chronic stress followed

by 4 month recovery, rats f L1 Laifenfeld et al., 2005 [169]

Stress, PFC21 days restrain stress, rats f total NCAM mRNA Venero et al., 2002 [152]21 days chronic CORT injection, rats f total NCAM expression Sandi and Loscertales, 1999 [135]6 weeks variable unpredictable chronic stress followed

by 4 month recovery, rats f L1 Laifenfeld et al., 2005 [169]

Depression Bipolar and major depression d soluble NCAM in cerebrospinal fluid Poltorak et al., 1996 [148]Bipolar and major depression (postmortem study) d L1 in PFC Laifenfeld et al., 2005 [150]

Antidepressants 21 days daily desipramine injections, rats d L1 in hippocampus and PFC Laifenfeld et al., 2005 [169]21 days daily fluoxetine injections, rats d L1 in hippocampus2 weeks daily rolipram administration, mice d PSA-NCAM in hippocampus Fujioka et al., 2004 [65]15 days daily fluoxetine treatment, mice d PSA-NCAM in hippocampus Encinas et al., 2006 [171]14 days fluoxetine treatment, rats d PSA-NCAM in PFC Varea et al., 2006 [172]Treatment of neuroblastoma cells with norepinephrine d L1 mRNA Laifenfeld et al., 2002 [173]Chronic imipramine treatment, rats d PSA-NCAM in hippocampus and PFC O’Leary et al., 2006 [170]

ExerciseLong-term moderate locomotor exercise, rats d NCAM and L1 mRNA in spinal gray matter Macias et al., 2002 [180]

LesionsLesions in the spinal cord, 3–5 days d L1 and d NCAM in Schwann cells Brook et al., 2000 [181]Postoperation, rats d NCAM in leptomeningeal cellsLesion in the entorhinal cortex d L1 on fibers of afferent innervating cells Styren et al., 1995 [182]

(deafferented dentate gyrus), 30 days postlesion, rats d NCAM on dendrites of denervated zoneLesion in the entorhinal cortex Jucker et al., 1996 [183]

(deafferented dentate gyrus), 65 days postlesion, rats d L1 afferent, reinnervating cellsExcitotoxic injury by kainic acid, 7 days after treatment, mice d PSA-NCAM in granular layer of dentate gyrus Dominguez et al., 2003 [184]Transient global ischemia in the medial temporal lobe,

1-7 days postocclusiond PSA-NCAM immunoreactive cells in hippocampus Fox et al., 2001 [185]

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hanced vulnerability to stress and depression. This view is further supported for other relevant life periods by re-cent evidence indicating that midlife stress in rats in-duced an accelerated cognitive decline during early aging in parallel with reduced hippocampal expression of NCAM [162] .

PSA-NCAM . The posttranslational modification of NCAM that involves � 2,8-linked polysialic acid (PSA) (see box 1) is also markedly affected by chronic stress. Chronically stressed rats were found to display increased hippocampal PSA-NCAM expression [151] , specifically apparent in the dentate gyrus [163] . However, when the stress regime was more persistent than the standard 3- to 4-week protocols (i.e., 6 weeks), no increase was observed in dentate gyrus PSA-NCAM levels [163] . Given the role of this molecule in neuritogenesis and synaptogenesis, increased hippocampal levels observed after 21 days of restraint stress was hypothesized to represent either com-pensatory or protective mechanisms against stress-in-duced neural damage [27] . The lack of increased PSA-NCAM reported at longer stress periods might re-flect exhaustion of the system to undergo compensatory changes when stress is maintained over a certain time period.

PSA-NCAM has been associated with newly generated cells [164, 165] and it plays a major role in the migration of new progenitors and neurons. As BDNF, PSA-NCAM was reported to enhance the differentiation and survival of newborn neurons [166, 167] . However, given that chron-ic stress actually decreases cell proliferation in the dentate gyrus, the increase of PSA-NCAM induced by stress can-not be attributed to a secondary effect on neurogenesis [154] . Importantly, chronic stress was also found to in-crease PSA-NCAM expression in the piriform cortex [168] , but to reduce it in several amygdala nuclei [30] .

L1 . Chronic stress in rats was found to result in in-creased L1 mRNA and protein expression in the hippo-campus, as evaluated 1 day after cessation of stress [151, 152] . Like NCAM, L1 is another cell adhesion molecule of the immunoglobulin superfamily that has been large-ly implicated in synaptic plasticity and memory for-mation (see boxes 1 and 2). Given the protective effects of this molecule, a neuroprotective role has been hy-pothesized for the stress-induced increases of L1 [27] . In line with this idea are also recent findings showing reduced L1 mRNA and protein levels in the frontal cor-tex and hippocampus (but not in the striatum) of rats exposed to chronic stress and examined 4 months later, a model simulating untreated depression-like patholo-gy [169] .

Cell Adhesion Molecules and Antidepressants Several recent studies have addressed the potential ef-

fects of antidepressants in PSA-NCAM expression. Over-all, chronic antidepressant treatments seem to enhance PSA-NCAM expression. Administration of rolipram, a drug that decreases the breakdown of the second mes-senger cyclic AMP (cAMP) and, thus, increases the func-tion and expression of the cAMP response element bind-ing protein (CREB) has been reported to have antidepres-sant activity in both animal models and clinical trials, as well as to increase hippocampal expression of PSA-NCAM in parallel with increased BDNF expression [65] . Chronic, but not acute, treatment with the tricyclic anti-depressant imipramine for 21 days in rats was also shown to increase the expression of PSA-NCAM in the hippo-campus and PFC [170] . An increase of PSA-NCAM in the hippocampal dentate gyrus by antidepressants was fur-ther confirmed after chronic treatment with the SSRI fluoxetine [171] .

The observation of increased PSA-NCAM in the PFC [170] is particularly important, given that, at difference to the hippocampus, this region is devoid of neurogene-sis. This suggests that chronic antidepressant treatment can also affect structural processes regardless of its ac-tions on neurogenesis. Such a possibility is further sup-ported by a recent study by Varea et al. [172] . These au-thors showed that fluoxetine treatment for 14 days in-creased the number of PSA-NCAM-immunoreactive neurons and neuropil immunostaining. Interestingly, co-administration of the 5-HT 3 antagonist ondansetron an-tagonized the effect of fluoxetine on PSA-NCAM expres-sion in the mPFC. These results implicate 5-HT 3 recep-tors on the effects of fluoxetine on hippocampal expression of PSA-NCAM.

In agreement with postmortem evidence that antide-pressants might counteract reduced L1 gene expression in some brain regions of depressed bipolar subjects (see above), animal studies confirmed the potential ability of antidepressants to modulate L1 expression. Thus, both in neuroblastoma cells as well as in the brain of rats chron-ically treated antidepressants, increased L1 gene expres-sion was reported [173] .

Another interesting observation is the fact that exer-cise, which has been shown to enhance neurogenesis [174, 175] and hypothesized to be a valid therapeutic approach to depression [176–179] , can upregulate NCAM and L1 expression. Macias et al. [180] showed that rats exposed to long-term moderate locomotor exercise, in addition to showing enhanced levels of BDNF, also presented in-creased expression of both adhesion molecules, as evalu-

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ated in the spinal gray matter. Further studies are needed to establish if similar increases can also be found in spe-cific brain regions.

The Link between Neural Cell Adhesion Molecules and Neurocircuitry Structure and Function

Changes induced by chronic stress in the expression of cell adhesion molecules ( tables 1 , 2 ) can have a prom-inent impact in neural structure and function. We re-view below available evidence indicating that changesin NCAM and L1 expression – and in NCAM pos trans-lational modifications – can be one of the main mecha-nisms which account for cognitive and neural dis-turbances observed in different stress models, andwhich have been related to the neurobiology of depres-sion.

Dendritic and Synaptic Remodeling As noted above, chronic stress results in reduced ex-

pression of NCAM (notably for the NCAM-140 isoform) in the hippocampus, an effect that might contribute to the structural shrinkage observed after chronic stress. Evidence for this hypothesis comes from different lines of evidence. First, as observed after chronic stress, den-dritic atrophy of CA3 pyramidal cells is accompanied by decreased NCAM expression after intracerebroventricu-lar injections of kainic acid in rats [186] . Second, NCAM

knockout mice display reduced thorny excrescences in CA3 pyramidal cells compared to their wild-type litter-mates [187] , a feature that also resembles the shrinkage in these complex spines observed after chronic stress. Third, NCAM is known to play a crucial role in the stabilization of synaptic contacts, with the NCAM-140 isoform being critically involved in neuritogenesis [188, 189] . Fourth, the NCAM-140 isoform was also reported to exert pro-tective actions against oxidative stress-related neuronal damage [190] . Therefore, we hypothesize that stress-in-duced reductions in NCAM expression (notably in the hippocampus) participate in the hippocampal atrophy observed in stress-related neuropsychiatric alterations (notably including depression).

Conversely, PSA-NCAM is increased in the rat hippo-campus after 3 weeks, but not 6 weeks, of chronic stress. PSA-NCAM plays a key role in neuritogenesis [164, 191] and synaptic plasticity [136] . It should be noted that in-creased levels of PSA-NCAM were always found in exper-iments in which brains were collected at least 24 h after the cessation of a 3-week stress period. Information on the ac-tual levels of PSA-NCAM during the chronic stress proce-dure is still missing. Therefore, the observed PSA-NCAM increase has been interpreted as either (i) a compensatory response to stress-induced neural damage [27, 151] or as (ii) a neuroprotective response disconnecting overstimu-lated synapses to protect relevant circuits from damage caused by excess glutamatergic input [192] . The possibil-ity that PSA-NCAM might be a compensatory mechanism to balance the reductions on BDNF induced by chronic stress was recently suggested [27] , given the proposed role for PSA-NCAM in ensuring an adequate sensitivity of neurons to BDNF [193, 194] . Conversely, once the system is exhausted (as it seems to occur after more enduring stress exposure), compensatory PSA-NCAM responses are not observed, which is line with behavioral evidence indicating that shorter periods of stress might serve adap-tive functions, while longer durations cause maladaptive changes [195] . The proposed neuroprotective role of PSA-NCAM in stress-related alterations is in line with the re-ported facilitation of PSA-NCAM expression by chronic antidepressant treatments [65, 170–172] .

As to L1, both stress-induced increases (immediate ef-fects) [151, 152] and decreases (when evaluated 4 months after stress cessation) [169] have been reported. L1 stimu-lates neurite outgrowth [112] , and has been implicated in repair processes in the lesioned adult CNS [112, 181] , in-cluding the deafferented dentate gyrus [182, 183] . There-fore, as hypothesized for PSA-NCAM, its immediate up-regulation after chronic stress might also represent a

Table 2. Regulation of cell adhesion molecules by chronic stress, antidepressants and mood disorders – summary of the main results presented in the text

NCAM L1 PSA-NCAM

Chronic stress f d dAntidepressants ?1 d dMood disorders ?2 d3 ?

1 Note that it remains to be tested whether the observed up-regulation of PSA-NCAM after antidepressant treatment is based on a reduction of total NCAM expression or rather a shift in the ratio of polysialylated versus non-polysialylated NCAM.

2 Note that the question remains as to whether or not increased soluble NCAM levels in cerebrospinal fluid might reflect reduced expression of this molecule in specific brain areas.

3 Although Laifenfeld et al. [150] found an increase in L1 ex-pression in both bipolar and major depressed patients (postmor-tem study) in the PFC, further studies in depressed patients will be needed to further clarify these findings.

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neuroprotective mechanism [27] to either protect or com-pensate from the deleterious effects induced by chronic stress [151, 152] . Therefore, reduced L1 expression ob-served in the PFC and in the hippocampus as a long-term effect of chronic stress might participate in structural at-rophy described for chronic stress and depression. This view fits with the ability of antidepressants to induce L1 expression [173] .

Hippocampal Neurogenesis NCAM and PSA-NCAM are crucially involved in pro-

liferation, migration and differentiation of neural pro-genitors [118, 196, 197] . Retrovirally transduced NCAM-140 isoform (the isoform that is particularly reduced by chronic stress) was shown to facilitate neuronal fate choice of hippocampal progenitor cells, facilitating neu-rogenesis via regulation of proneurogenic transcription factors [198] . Cell culture experiments have shown that removal of PSA from NCAM induces neuronal differen-tiation via heterophilic NCAM interactions at cell con-tacts [196] . Removal or blockade of PSA was also found to lead to a marked decrease in neurogenesis in an in vitro model [165] . Moreover, in vitro neurogenesis was also im-paired in cell cultures prepared from NCAM knockout mice [165] . Further experiments including the prolifera-tion marker BrdU and the enzyme endoneuroaminidase (endo-N), that specifically cleaves PSA from NCAM, in-dicated that PSA affects neurogenesis through an action on the early survival of newly generated neurons, not on the mitotic activity of progenitors [165] .

Functional Implications: Structural Plasticity and Behavior In addition to the structural disconnection, the net-

work hypothesis of depression implies the occurrence of problems in information processing within relevant neurocircuits [7] . Alterations in the expression levels of NCAM can certainly impair neural communication, as shown by different lines of evidence indicating that in-terfering with NCAM function impairs synaptic plas-ticity in the hippocampus. First, incubation of hippo-campal slices with either NCAM antibodies or peptides that disrupt NCAM homophilic or heterophilic adhe-sion was shown to block LTP induction the CA1 region without affecting basal synaptic transmission [116, 124] . Second, constitutional NCAM knockout mice showed impaired LTP in both CA1 [136, 193] and CA3 [115] hip-pocampal subregions. Third, impaired synaptic plastic-ity resulting from NCAM reduction was also confirmed for LTP and LTD in CA1 in mice presenting a condi-

tional ablation of NCAM gene in adulthood [130] . At the cognitive level, interfering with NCAM, PSA-NCAM or L1 function has been repeatedly shown to result in marked learning and/or memory impairments, with many examples indicating a prominent role of these molecules in hippocampus-dependent information pro-cessing (see box 2).

Available information about the behavioral phenotype of constitutive NCAM knockout mice indicates that these animals present certain features indicative of vulnerabil-ity to develop depression, such as behavioral inhibition [199] , enhanced anxiety [200] , and increased intermale aggression [132, 200] . Behavioral inhibition was also found after injecting rats with a synthetic peptide, C3d, that blocks NCAM homophilic binding [201] . Moreover, NCAM knockout mice show enhanced stress-induced ac-tivation of corticosterone levels [199] , which fits with a frequently observed dysregulation of the HPA axis in de-pression. However, these mice failed to show depression-like behavior in one of the pharmacologically-validated models of depression, the forced swim test [132] . In any case, this particular lack of evidence should be taken cau-tiously, given that these constitutive NCAM knockout mice show some developmental problems [187] and there is a total removal of NCAM, which is not the case in mod-els of stress-induced disorders in which there is a reduc-tion, not a complete abolishment. The ideal test would be to evaluate the behavior of available conditional NCAM knockout mice [130] in a variety of models of depression.

A Model for the Role of the Neural Cell Adhesion Molecules NCAM and L1 in Stress-Related Mood Disorders

As stated above, a neurotrophic model has been pro-posed to account for stress-related mood disorders [83] and speculated to contribute to the network hypothesis of depression [7] . The idea is that reductions in BDNF, along with alterations in other neurotrophic/growth factors (in-cluding VEGF and FGF2) may contribute to the patho-physiology and/or treatment of depression [83] ( fig. 2 ). Moreover, these recent hypotheses sustain that alteration in the levels of these molecules are not directly responsible for the core symptoms of depression. Instead, they are re-garded as crucial factors for mediating changes in a vari-ety of features of neural plasticity (including structural remodeling, synaptic stabilization, and neurogenesis) that eventually determine the quality of information process-ing [83] .

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Evidence included in this review led us to propose the neural cell adhesion molecules NCAM and L1 as poten-tial key partners of these neurotrophic/growth factors in mediating the functional alterations in relevant neurocir-cuits that occur in both stress-related mood disorders and antidepressant actions. In particular, the consistent-ly reported stress-induced reduction of NCAM in the hippocampus (but also in other areas, including the PFC) might be critical for two of the critical features of the net-

work theory of depression, namely structural remodeling (e.g., dendritic atrophy, synaptic reduction, and atrophy of thorny excrescences) and neurogenesis (see above for evidence). Moreover, evidence from the functional impli-cations of NCAM (see box 2) indicates that reductions in this molecule will affect neural circuits by impairing syn-aptic plasticity and cognitive function, which are also critical factors in the information processing theory of depression ( fig. 2 ). NCAM binding to and activation

Fig. 2. Involvement of neurotrophic/growth factors and cell ad-hesion molecules in the pathophysiology of stress and depression (modified from Duman and Monteggia [83] to implement cell adhesion molecules in the model of key mechanisms mediating depression and antidepressant actions). a Prolonged stress and long-lasting elevated glucocorticoid levels have been shown to de-crease levels of the neurotrophic factors (VEGF and BDNF), as well as of NCAM mainly in the hippocampus, but also in the PFC. The altered expression of these proteins lead to neuronal atrophy in CA3 pyramidal neurons and reduced neurogenesis in the den-

tate gyrus (DG), which may contribute to behavioral and cogni-tive alterations observed after stress and in depressed patients. b In contrast, antidepressants have been shown to restore neuro-nal atrophy and to induce neurogenesis, potentially by increasing the expression of these growth factors, as well as to enhance the expression of L1 and PSA-NCAM in the hippocampus and the PFC. The upregulation of L1 and PSA-NCAM by antidepressant treatment, may potentially facilitate recovery form stress-induced depression.

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(phosphorylation) of fibroblast growth factor receptor 1 (FGFR1) [202] followed by calcium entry [203] has been identified as a mechanism whereby NCAM promotes neuronal differentiation and neuritogenesis [118] .

Therefore, we hypothesize that reductions in hippocam-pal and PFC NCAM levels might be critical for stress-in-duced depression. A prediction derived from this proposal would be that stimulating the NCAM binding site in FGFR should counteract for the deleterious effects of chronic stress (and depression) in neuronal processing, cognitive function and behavioral alterations. This prediction can nowadays be tested with a recently developed peptide, FGL [202] that, in fact, was already proved to be effective to pro-mote cognitive function in undisturbed (non-stressed) rats [204] . A second prediction would be that either condition-ally deleting/reducing or silencing the NCAM gene (par-ticularly NCAM140 isoform) in the hippocampus (and po-tentially also in the PFC) should render individuals par-ticularly susceptible to the deleterious effects of stress, both in neural structure and function. Ideally, such a manipula-tion should result in depression-like behavior.

Our model also hypothesizes that the posttranslation-al modification of NCAM, PSA-NCAM, and L1 might be important molecular targets in hippocampus and mPFC to facilitate recovery from stress-induced depression. Both molecules have been largely implicated in neuronal repair and regeneration [113, 184, 185] , and both were re-ported to be increased by antidepressant treatments (in addition to clinical and preclinical evidence implicating reduced L1 in bipolar disorder and chronic stress induced alterations). Interestingly, PSA-NCAM has been pro-posed to play a role in enabling an adequate sensitivity of neurons to BDNF [193, 194] , which further supports its role in the network hypothesis of depression. A critical prediction deriving from this hypothesis is that either ge-

netic deletion or pharmacological inactivation of these molecules should promote stress-induced depression-like structural, cognitive and behavioral alterations. Al-though, to our knowledge, specific depression tests have not been performed as yet following such experimental manipulations, recent evidence in PSA-NCAM-deficient mice indicate that a deficit in this molecule can lead to cognitive deficits in hippocampus [205, 206] and PFC [206] dependent tasks, which are in line with some cogni-tive deficits associated with depression. A second predic-tion would be that individual differences in the expres-sion levels or functionality of these molecules might have an important impact in the individuals’ vulnerability to develop and/or recover from mood disorders.

As compared to the extensive knowledge accumulated over the past two decades on the functional implications of neurotrophins, information about the cell adhesion molecules is still rather limited. Therefore, it is important to mention that some of the evidence presented here to support our model to implicate cell adhesion molecules in stress-related mood disorders is derived from isolated studies, and that caution should be taken before new studies replicating these findings are reported. We have presented here a model incorporating NCAM and L1 onto the network theory of depression, including specific predictions (some of them being currently tested in our laboratory) that can be evaluated with the available meth-odologies. We expect major advances occurring in this field in the next coming years.

Acknowledgements

This work was partially supported by grants from the Swiss Na-tional Science Foundation (3100A0-108102) and the EU 6th Frame-work Programme (PROMEMORIA LSHM-CT-2005-512012).

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

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