Pharmacological Reports Copyright © 2013 2013, 65, 1471–1478 by Institute of ISSN 1734-1140 Polish Academy of Sciences

Review

PotentialrolesofNCAM/PSA-NCAMproteins indepressionandthemechanismofaction of

KrzysztofWêdzony,AgnieszkaChocyk,MarzenaMaækowiak

Laboratory of Pharmacology and Brain Biostructure, Department of Pharmacologcy, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Correspondence: Krzysztof Wêdzony, e-mail: [email protected]

Abstract: Recently, it has been proposed that abnormalities in neuronal structural plasticity may underlie the pathogenesis of major depression, resulting in changes in the volume of specific brain regions, including the hippocampus (HIP), the prefrontal cortex (PC), and the amygdala (AMY), as well as the morphology of individual in these brain regions. In the present survey, we compile the data regarding the involvement of the neural cell adhesion molecule (NCAM) protein and its polysialylated form (PSA-NCAM) in the pathogenesis of depression and the mechanism of action of antidepressant drugs (ADDs). Elevated expression of PSA-NCAM may reflect neuroplastic changes, whereas decreased expression implies a rigidification of neuronal morphology and an impedance of dy- namic changes in synaptic structure. Special emphasis is placed on the clinical data, genetic models, and the effects of ADDs on NCAM/PSA-NCAM expression in the brain regions in which these proteins are constitutively expressed and neurogenesis is not a major factor; this emphasis is necessary to prevent cell proliferation and neurogenesis from obscuring the issue of brain plasticity.

Keywords: antidepressantdrugs,depression,NCAM,PSA-NCAM

Abbreviations: ADD – antidepressant , ADDs – antide- ogical effect of these drugs, i.e., the blockade of sero- pressants, antidepressant drugs, AMY – amygdala, FGFR – fi- tonin and noradrenaline uptake, is not clearly associ- broblast growth factor , FLU – fluoxetine, HIP – hip- ated with their clinical efficacy [30]. Moreover, the pocampus, NCAM – neural cell adhesion molecule, PC – pre- frontal cortex, PSA – 2,8-polysialic acid, PSA-NCAM – novel antidepressant (ADD) is actually polysialylated form of neural cell adhesion molecule, SPT su- a enhancer [32]. In addition, the crosepreferencetest, TST – tailsuspensiontest direct, rapid effect of ADDs on monoamines contrasts with the delayed onset of effectiveness of ADDs in the clinic [30]. Recent theories on the pathogenesis of major depression suggest that changes in neuronal Introduction plasticity may be responsible for the appearance of depressive symptoms and that ADDs alleviate symp- The hypothesis that toms by interfering with the mechanism responsible (ADDs) act via inhibition of monoamine uptake has for plasticity of neuronal morphology [36]. These been called into question [30]. First, the pharmacol- changes may reflect alterations in neuronal structure,

Pharmacological Reports, 2013, 65, 1471–1478 1471 leading to disturbances in the balance of excitatory NCAM) as a cause of depression and potential target and inhibitory [15]. It has been forADDs. demonstrated in animal models that chronic stress Essentially, cell adhesion molecules help cells stick [35, 36] induces dendritic atrophy and reductions in to each other and their surroundings. NCAM is spine density in principal neurons of the hippocampus a member of the immunoglobulin (Ig) superfamily of (HIP) [31] and the medial prefrontal cortex (PC) [40]. adhesion molecules, which are encoded by a single Although it is not known whether prolonged stress is gene. The process of alternative splicing can yield sufficient to evoke depression, it is often considered two transmembrane NCAM isoforms – one 180- or as a precipitating factor for depression in humans. 140-kDa isoform – or one 120-kD glucophosphatidyl Nevertheless, when chronic stress models are used inositol-linked isoform. The extracellular domain of with an understanding of the limitations, they can pro- NCAM is composed of five Ig-like domains followed vide powerful information about the underlying mo- by two fibronectin type III (FN3) domains. NCAM exhibits two modes of binding: homophilic and het- lecular and cellular determinants of anatomical altera- erophilic. Homophilic binding consists of linkages to tions in neuronal circuitry, which controls complex a series of counter-receptors, including tyrosine ki- stress-related behaviors [36]. Certain types of pro- nase receptors, such as the fibroblast growth factor re- longed stress, such as learned helplessness and ceptor (FGFR), the brain-derived neurotrophic factor chronic mild unpredicted stress, are accepted as real- receptor, and the tropomyosin kinase receptor B. Het- istic depression models [36]. These models indicate erophilic binding, i.e., linkages to other adhesion that it is not the stress per se but rather an inability to molecules and various extracellular NCAMs, is also cope with stress that leads to depression [11]. Thus critical for maintenance of proper neuronal connec- far, there are limited studies with data indicating that tions. To bind 2,8-polysialic acid (PSA), NCAM at- there is a reduction in neuronal size, spine density, or taches to the negatively charged long chains of PSA, density in realistic models of depression conferring anti-adhesive properties on the molecule. (chronicmildstress,learnedhelplessness)[2,33]. A high degree of NCAM polysialylation on neuronal In the last decade, an impressive body of clinical processes promotes a variety of developmental data has been collected using imaging techniques to events, such as axonal growth and fasciculation, cell examine the morphological and metabolic brain migration, initiation of synaptic reorganization, and changes that are characteristic of depression [3, 10, synaptogenesis. The expression of PSA-NCAM is 24]. Meta analyses (essential for reviewing findings particularly high in the developing brain, as well as in from different studies and comparing results in a stan- adults in the brain regions that undergo persistent and dardized fashion) investigating the changes in voxel- sustained synaptic plasticity, such as the hypotha- based morphometry have lead to the conclusion that, lamo-neurohypophysial system, the olfactory bulb, in the course of depression, there are significant de- the medial prefrontal, piriform and entorhinal corti- creases in morphological volume within the cortico- ces, the AMY, and the HIP. Thus, alterations in the ex- limbic circuit, including the amygdala (AMY), the pression of PSA-NCAM may signify that changes in fronto-medial cortex, the paracingulate cortex, and, plasticity are occurring in the adult brain (for exam- depending on the analysis, the HIP [3, 10, 24]. Al- ples from our laboratory, see [5, 25–27]). Elevated ex- though it is not clear whether the observed changes in pression of PSA-NCAM may reflect changes in plas- human brain volume are causative to depression, they ticity, whereas decreased expression implies a rigidifi- raise an interesting question regarding the cause and cation of neuronal morphology and an impedance of effect between plasticity and depression. Shrinkage of dynamic changes in synaptic structure (for a extensive the brain structure, as well as the size of individual reviewonNCAM/PSA-NCAM,see[12,14]). neurons, is also observed in chronically stressed ani- mals [31, 40]. In the present article, we focus our at- tention on the superfamily of adhesion molecules, which are proteins located on the cell surface that are Clinicaldata involved in binding with other cells or with the extra- cellular matrix in a process called cell adhesion. Spe- cifically, we consider the neural cell adhesion mole- Clinical evidence regarding the involvement of cule (NCAM) and its polysialylated form (PSA- NCAM proteins in depression and bipolar disorders is

1472 Pharmacological Reports, 2013, 65, 1471–1478 NCAM/PSA-NCAMproteinsindepression Krzysztof Wêdzony et al.

sparse thus far. The soluble form of NCAM proteins acid-long , called FGL. The FGL peptide mim- was detected in cerebrospinal fluid for the first time in ics the interaction of NCAM with fibroblast growth 1988 by Jorgensen [21] and further replicated by Pol- factor receptors (FGFR), suggesting a novel therapeu- torak et al. in 1996 [38]. Both reports indicated an in- tic target for drugs aimed at treatment of depression creased concentration of the soluble form of NCAM [22]. Although the cognitive impairments observed in in psychiatric patients suffering from bipolar mood the NCAM–/– model may be regarded as models of disorder and major depression. Importantly, Poltorak indecisiveness which accomplishes depression, on found no effect of on NCAM concentra- one hand, on the other hand, they could interfere with tion (primarily the 120-kDa isoform) [38]. This ap- animals’ performance on test assessments evaluating parent effect raises the question of disease specificity. their depressive state. This confound has been re- Unfortunately, a similar effect has been observed in solved using NCAM +/– heterozygous mice [23]. patients suffering from schizophrenia [45], suggesting Again, such NCAM +/– animals display depres- a common effect of schizophrenia and depression on sive-like symptoms in the TST, the SPT, and the brain plasticity, rather than a disease-specific pathol- novelty-suppressed feeding test; however, NCAM +/– ogy marked by apparently abnormal NCAM turnover mice are devoid of cognitive impairments [23]. It is in the CNS of patients with mood disorders. However, worth noting here that NCAM–/– animals has exhibit depressed patients exhibited decreased PSA-NCAM an increased level of fear and anxiety [22], which is expression in the basolateral and basomedial AMY observed in the course of depression, and their re- [44], while bipolar patients showed the opposite effect duced ability to cope with stress what may result [44], as measured by stereological procedures. These againintheirdepressivevulnerability[1]. effects have now been reproduced by western blot [28]. Interestingly, studies performed on brains do- nated by the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients, no changes in PSA-NCAM ImpactofADDsonexpression expression were observed in PC tissue of bipolar and ofNCAM/PSA-NCAMprotein depressedpatients[15].

Thus far, we have found five separate articles demon- strating the impact of ADDs on expression of NCAMgeneknockoutasamodel NCAM/PSA-NCAM protein (see Tab. 1 and its refer- ofdepression ences). These studies are based on chronic ADDs ad- ministration [fluoxetine (FLU) (four reports) and imi- The transgenic animal model knocking out the gene pramine (one study) – see Tab. 1 and references encoding the NCAM proteins is a useful tool to verify there)]. In all the studies mentioned, elevated expres- its role as a potential cause of depression. Mice lack- sion has been noted in both young-adult and adult ani- ing all three major isoforms of NCAM (NCAM–/–) mals. Such consistent effects have been observed in exhibit citalopram- and amitriptyline-sensitive anhe- the PC or its subregions, while decreased expression donia measured by the sucrose preference test (SPT) has been noted in the AMY in adult but not adolescent [1]. In the tail suspension test (TST), an assessment rats (see Tab. 1 and its references). Animal age is im- designed test invented to screen for the ADDs activ- portant because constitutive expression of NCAM/ ity, NCAM–/– animals exhibit an increased time of PSA-NCAM is decreased during the life span [12, immobility in comparison to their respective controls. 14]. An additional 3 separate experiments utilized The above effect has been blocked/attenuated by the a stress model, and both the ADD FLU and the novel classic ADDs amitriptyline and citalopram [22]. ADD, agomelatine, were found to influence stress- These findings indicate that a lack of NCAM proteins induced elevation of NCAM/PSA-NCAM. Two studies is sufficient to evoke “depressive-like” behavior, but indicated that stress elevates the expression of NCAM is not sufficient to influence the therapeutic effect of protein in the PC and the HIP, which is blocked by ADDs [22]. The effect of NCAM knockout in the chronic administration of FLU [8, 9]. Agomelatine TST and SPT has also been reversed by a 15-amino [39] normalized the stress- and learning-induced de-

Pharmacological Reports, 2013, 65, 1471–1478 1473 Tab. 1. Impact of various antidepressant drugs on expression of NCAM or PSA-NCAM proteins in the rat brain

Antidepressant Species Methodofanalysis Paradigm Brainregion Effect Ref. drug(dosage andtreatment)

Fluoxetine, Young-adult Westernblot,NCAM Chronicsocial PC ReductionofthePSA-NCAM [8] 21days, male isolation levelelevatedbystress. 5mg/kg ip Wistarrats Innaive,noeffect

Fluoxetine, Young-adult Immuno-cytochemistry, Naive PC,AMY, Increaseinallanalysedregions [17] 14days, male PSA-NCAM HIP 10mg/kg ip Wistarrats

Fluoxetine, Young-adult Westernblot Chronicsocial HIP ReductionofthePSA-NCAM [9] 21days, male isolation levelelevatedbystress. 5mg/kgip Wistarrats Alone,inactive

Fluoxetine, Youngand Immuno-cytochemistry, Naive AMY,DR, AMY-increasedinadolescent [19] 21days, oldmale NCAM/PSA-NCAM PC butdecreasedinadult. 12mg/kg po Wistarrats Noeffectsintheother brainregions

Agomelatine, Adultmale Immuno-cytochemistry Spatialmemory vHIP Treatmentblockedthewater [7] 22days, Sprague- training maze-induceddecreasein 10mg/kg ip Dawleyrats withorwithout PSA-NCAMinbothstressed predatorstress andnon-stressedanimals

Fluoxetine, Adultmale Immuno-cytochemistry Naive PC,AMY IncreasedPSA-NCAM [44] 14days, Sprague- expressioninPC 10mg/kg, ip Dawleyrats anddecreasedinAMY

Imipramine, Adultmale Immuno-cytochemistry, Naive PEC,PIC, Increaseonlyafter [41] acute30mg/kg ip Wistarrats PSA-NCAM HIP chronictreatment andchronic, 21days, 15mg/kg ip

Fluoxetine, Young-adult Immuno-cytochemistry, Naive INC,PRC, Increase [43] 14days, male PSA-NCAM CC 10mg/kg ip Wistarrats

The table was developed using data compiled from a Medline search based on the following key words: antidepressant drugs and PSA-NCAM and antidepressant drugs and NCAM. Two articles were omitted because they address the question of proliferation but not neuroplastic changes. Abbreviations: AMY – amygdala, CC – cingulate cortex, DR – dorsal raphe nucleus, HIP – hippocampus, INC – infralimbic cortex PC – prefrontal cortex, PEC – perilimbic cortex, PIC – piriform cortex, PRC – prelimbic cortex, vHIP – ventral hippocampus, ip – intraperitoneal route of drug administration po – oral administration (per os)

creases in expression of PSA- NCAM observed in the example, transmission. To our knowl- ventralHIP. edge, only one study addresses this issue. It has been Apart from the phenomenological observation that found that acute administration of ondansetron, a spe- ADDs (predominately FLU) alters the expression of cific antagonist of 5-HT3 receptors, in an acute dose PSA-NCAM proteins, relatively little is known about alleviated the increase in PSA-NCAM induced by the mechanism of above effects. Is not clear whether chronic FLU administration [43]. This result appears ADDs, or FLU specifically, directly influences PSA- to suggest that FLU alters PSA-NCAM via changes in NCAM or NCAM expression or leads to changes in serotonergic transmission and in a manner that in- expression via alterations in neurotransmission – for volved5-HT3 receptors[43].

1474 Pharmacological Reports, 2013, 65, 1471–1478 NCAM/PSA-NCAMproteinsindepression Krzysztof Wêdzony et al.

Finally, it bears mentioning two published articles rection was a study by Bessa at al. [2] demonstrating that utilized the ability of ADDs to induce neuroplas- that chronic mild stress leading to anhedonia (de- tic changes in a manner that is clearly distinct from creased sucrose preference) provoked an increase in their ADDs properties [13, 20]. The first study ana- the expression of NCAM mRNA in the rat nucleus ac- lyzed the impact of on alteration of NCAM expres- cumbens. This effect was reversed by chronic admini- sion in the HIP after kainic acid-induced seizure [20], strationofFLUandimipramine[2]. and the second study analyzed the effect of prolonged administration of venlafaxine on alteration of NCAM expression in ischemic stroke [13]. Administration of kainic acid induces seizures and neuronal death NCAMaspotentialtargetfornew largely in CA3 region, followed by a cascade of neu- antidepressants roplastic changes throughout the HIP, including tem- porary activation of neurogenesis, dispersion of gran- ule cells, and reorganization of mossy fibres [20]. All It is difficult to imagine that molecules of extracellu- of the above changes have been restored to control lar matrix could be targets for novel ADDs. However, levels after administration of citalopram seven days drugs that may alter brain structure are of potential in- before and 21 days after administration of kainic acid. terest not only in the case of depression but also in It is also not clear whether citalopram directly influ- several other disorders associated with either cogni- ences neuroplastic changes or neuroplastic changes tion or learning and memory. In the case of NCAM are attenuated by a decrease in seizure severity. The proteins, it may be proposed that inhibitors or activa- mechanism through which ADDs could alter seizure- tors of the polysialyltransferases ST8SiaII (STX) and evoked neuroplasticity is largely unknown. It has ST8SiaIV (PST), selectively involved in polysialyla- been speculated that the effectiveness of ADDs ad- tion of the NCAM protein may constitute a potential ministered in a course typical for treatment of depres- drug target. As mentioned above, long negatively sion (i.e., chronic administration) is not only due to charged chains of PSA attached to NCAM confer changes in concentrations and/or re- anti-adhesive properties to the molecule and promote ceptor sensitivity but is also due to an improvement in reorganization of the mature brain [12, 14]. STX brain plasticity and tissue remodelling [20]. There is regulates NCAM polysialylation during embryonic, one study analyzing the impact of chronic venlafaxine perinatal, and early postnatal development, whereas on expression of NCAM proteins in the mouse HIP PST is predominantly active in the postnatal brain [4, after cerebral ischemia [13]. The rationale of these ex- 29]. The data indicating that depression results from periments is based on the assumption that ischemic developmental origin, or traumatic life events STX brain injury often results in severe neurological dam- and PST are the targets of choice. It is not known age, which may be the basis for the accompanying whether animals with the gene encoding STX or PST cognitive impairment and depressive states [13]. It knocked out are “depressive” [4, 29]. Thus far, it has has been observed that venlafaxine in a dose- been observed that they display specific impairments dependent manner abrogates the ischemia-induced in spatial memory but not conditioned fear memory in elevation of NCAM proteins in the HIP [13]. It will be PST knockouts [29]. It has also been found that both of interest to further analyze the above pathway to in- STX and PST knockouts exhibit impaired sociability, vestigate first, whether ischemic insults in mice lead while only STX exhibits an increased level of aggres- to depressive symptoms and, secondly, whether acute sion and enhanced stress reactivity, as measured by or prolonged administration of venlafaxine after corticosterone levels in response to stress [4]. Alter- ischemic insults is also effective against the ische- natively, alteration in the level of the circulating solu- mia-induced elevation of PSA-NCAM. The results of ble form of NCAM may be another target. Soluble both studies may indicate that ADDs may be used ef- NCAM is an antagonist of membrane-bound NCAM. fectively in brain disorders caused by abnormalities in This antagonism can be achieved by either a specific neuroplasticity[13,20]. antibody or a compound that influences or detaches In summary, the data indicating a role of NCAM or the constitutive membrane-bound NCAM. The family PSA-NCAM proteins in realistic models of depres- of ADAM (a disintegrin and metalloproteinase) pro- sion are yet to be discovered. The first step in that di- teins is required for NCAM shedding and may consti-

Pharmacological Reports, 2013, 65, 1471–1478 1475 tute a potential target for novel drugs [18]. Finally, small population of these cells express parvalbumin, linkage of NCAM to FGFRs is of potential interest. calretinin, and neuropeptide Y or vasointestinal pep- The ability of the FGL peptide to penetrate the CNS tide [16, 34]. Additionally, PSA-NCAM-positive cells after peripheral administration supports further re- in the neurophil co-expressed markers of GABAergic search of NCAM proteins as targets of novel ADDs terminals and neurotransmission, such as the vesicular [1,42]. GABA transporter (VGAT) or GAD67, but virtually none of them expressed the vesicular glutamate trans- porter 1 (VGLUT1), a marker of neu- rons [16, 34]. The above characteristics are given here because they provide important information regarding Conclusion the potential mechanism of action of ADDs. It is con- ceivable that via alteration in structural plasticity gov- Although the concept that depression and the mecha- erned by PSA-NCAM, ADDs may shift the balance nism of action of ADDs are associated with remodel- between inhibitory input and excitatory output in neu- ling of neuronal circuits that are essential for mood ronalcircuitsassociatedwithdepression. and cognition is interesting, it should, however, be suggested cautiously [36]. First, only a limited number of clinically effective ADDs have been tested Acknowledgment: This work was supported by grant no. POIG.01.01.02.-12-004/09 (Tab. 1). Secondly, limited, if any, studies analyzed “Depression-Mechanism-Therapy” (part 2.2. to MM). the time course of changes in expression of PSA-NCAM/NCAM after ADD treatment, and there- fore, it is not clear whether the described effects are transient or persistent. In the absence of clear clinical References: data regarding the involvement of NCAMs in the eti- ology of depression, it is conceivable that these pro- 1. Aonurm-HelmA,JurgensonM,ZharkovskyT,SonnK, teins may be involved in the mechanism of action of BerezinV,BockE,ZharkovskyA:Depression-likebe- ADDs but not in the origination of depression. Thus haviourinneuralcelladhesionmolecule(NCAM)-def- far, the most probable explanation for the effect of icientmiceanditsreversalbyanNCAM-derivedpep- tide,FGL.EurJNeurosci,2008,28,1618–1628. ADDs is that they alter serotonergic transmission, 2. BessaJM,MoraisM,MarquesF,PintoL,PalhaJA, precipitating brain remodelling [43]. Subsequently, it AlmeidaOF,SousaN:Stress-inducedanhedoniaisasso- will be necessary to investigate symptoms of depres- ciatedwithhypertrophyofmediumspinyneuronsof sion in animal models overexpressing the soluble thenucleusaccumbens.TranslPsychiatry,2013,3,1–7. 3. form of NCAM. Such animals are available and dis- BoraE,FornitoA,PantelisC,YucelM:Graymatterab- normalitiesinMajorDepressiveDisorder:ameta- play a schizophrenic-like phenotype [37]. However, analysisofvoxelbasedmorphometrystudies.JAffect the common feature of schizophrenia and depression Disord,2012,138,9–18. on the level of mood does not rule out depressive 4. CalandreauL,MarquezC,BisazR,FantinM,SandiC: symptoms. Finally, it will be important to confirm the DifferentialimpactofpolysialyltransferaseST8SiaIIand effects of both chronic and acute administration of ST8SiaIV knockoutonsocialinteractionandaggression. GenesBrainBehav,2010,9,958–967. ADDs. The latter suggestion is important in the con- 5. ChocykA,DudysD,PrzyborowskaA,MaækowiakM, text of experiments performed on C6 glioma cells that WêdzonyK:Impactofmaternalseparationonneural indicated that even short exposure of these cells to celladhesionmoleculesexpressionin FLU, such as 6 hours, increased expression of the brainregionsofjuvenile,adolescentandadultrats. NCAM protein [6]. NCAM/PSA-NCAM positive PharmacolRep,2010,62,1218–1224. 6. ChoiMR,OhDH,KimSH,JungKH,DasND, cells are present predominately, if not exclusively, in ChaiYG:Fluoxetineincreasestheexpressionof the population of inhibitory interneurons located in NCAM140andpCREBinratC6gliomacells.Psychia- the PC, AMY, and HIP. PSA-NCAM-expressing cells tryInvestig,2012,9,180–186. 7. constitute around 10% of the GAD67-expressing in- ConboyL,TanrikutC,ZoladzPR,CampbellAM, ParkCR,GabrielC,MocaerEatal.:Theantidepressant terneurons, i.e., GABAergic inhibitory interneurons agomelatineblockstheadverseeffectsofstressonmem- [16, 34]. Many of the PSA-NCAM-expressing somata oryandenablesspatiallearningtorapidlyincreaseneu- are positive for calbindin and somatostatin, and a very ralcelladhesionmolecule(NCAM)expressioninthe

1476 Pharmacological Reports, 2013, 65, 1471–1478 NCAM/PSA-NCAMproteinsindepression Krzysztof Wêdzony et al.

hippocampusofrats.IntJNeuropsychopharmacol,2009, 21. JorgensenOS:Neuralcelladhesionmolecule(NCAM) 12,329–341. andprealbuminincerebrospinalfluidfromdepressedpa- 8. DjordjevicA,DjordjevicJ,ElakovicI,AdzicM,Matic tients.ActaPsychiatrScandSuppl,1988,345,29–37. G,RadojcicMB:Effectsoffluoxetineonplasticityand 22. JurgensonM,Aonurm-HelmA,ZharkovskyA:Behav- apoptosisevokedbychronicstressinratprefrontalcor- ioralprofileofmicewithimpairedcognitionintheele- tex.EurJPharmacol,2012,693,37–44. vatedplus-mazeduetoadeficiencyinneuralcelladhe- 9. DjordjevicA,DjordjevicJ,ElakovicI,AdzicM,Matic sionmolecule.PharmacolBiochemBehav,2010,96, G,RadojcicMB:Fluoxetineaffectshippocampalplastic- 461–468. ity,apoptosisanddepressive-likebehaviorofchronically 23. JurgensonM,Aonurm-HelmA,ZharkovskyA:Partial isolatedrats.ProgNeuropsychopharmacolBiolPsychia- reductioninneuralcelladhesionmolecule(NCAM)in try,2012,36,92–100. heterozygousmiceinducesdepression-relatedbehaviour 10. DuMY,WuQZ,YueQ,LiJ,LiaoY,KuangWH,Huang withoutcognitiveimpairment.BrainRes,2012,1447, XQatal.:Voxelwisemeta-analysisofgraymatterreduc- 106–118. tioninmajordepressivedisorder.ProgNeuropsycho- 24. LaiCH:Graymattervolumeinmajordepressivedisor- pharmacolBiolPsychiatry,2012,36,11–16. der:ameta-analysisofvoxel-basedmorphometrystud- 11. DumanCH:Modelsofdepression.VitamHorm,2010, ies.PsychiatryRes,2013,211,37–46. 82,1–21. 25. MaækowiakM,ChocykA,DudysD,WedzonyK:Acti- 12. ElMA,RutishauserU:UseofPSA-NCAMinrepairof vationofCB1receptorsimpairsmemory thecentralnervoussystem.AdvExpMedBiol,2010, consolidationandhippocampalpolysialylatedneuralcell 663,137–147. adhesionmoleculeexpressionincontextualfearcondi- 13. FangS,YanB,WangD,BiX,ZhangY,HeJ,XuHet tioning.Neuroscience,2009,158,1708–1716. al.:Chroniceffectsofvenlafaxineonsynaptophysinand 26. MaækowiakM,DudysD,ChocykA,WedzonyK: neuronalcelladhesionmoleculeinthehippocampusof Repeatedrisperidonetreatmentincreasestheexpression cerebralischemicmice.BiochemCellBiol,2010,88, ofNCAMandPSA-NCAMproteinintheratmedialpre- 655–663. frontalcortex.EurNeuropsychopharmacol,2009,19, 14. GasconE,VutskitsL,KissJZ:Polysialicacid-neuralcell 125–137. adhesionmoleculeinbrainplasticity:fromto 27. MaækowiakM,GrzegorzewskaM,BudziszewskaB, integrationofnewneurons.BrainResRev,2007,56, ChocykA,HessG,WêdzonyK:Cocainedecreasesthe 101–118. expressionofPSA-NCAMproteinandattenuateslong- 15. Gilabert-JuanJ,VareaE,GuiradoR,Blasco-IbanezJM, termpotentiationviaglucocorticoidreceptorsintherat CrespoC,NacherJ:Alterationsintheexpressionof dentategyrus.EurJNeurosci,2008,27,2928–2937. PSA-NCAMandsynapticproteinsinthedorsolateral 28. MaheuME,DavoliMA,TureckiG,MechawarN: prefrontalcortexofpsychiatricdisorderpatients.Neuro- Amygdalarexpressionofproteinsassociatedwithneuro- sciLett,2012,530,97–102. plasticityinmajordepressionandsuicide.JPsychiatr 16. Gómez-ClimentMA,GuiradoR,Castillo-GómezE, Res,2013,47,384–390. VareaE,Gutierrez-MecinasM,Gilabert-JuanJ,Garcia- 29. MarkramK,Gerardy-SchahnR,SandiC:Selective MompóCetal.:Thepolysialylatedformoftheneural learningandmemoryimpairmentsinmicedeficientfor celladhesionmolecule(PSA-NCAM)isexpressedina polysialylatedNCAMinadulthood.Neuroscience,2007, subpopulationofmaturecorticalinterneuronscharacter- 144,788–796. izedbyreducedstructuralfeaturesandconnectivity. 30. MassartR,MongeauR,LanfumeyL:Beyondthe CerebCortex,2011,21,1028–1041. monoaminergichypothesis:neuroplasticityandepige- 17. GuiradoR,Sanchez-MatarredonaD,VareaE,CrespoC, neticchangesinatransgenicmousemodelofdepression. Blasco-IbanezJM,NacherJ:Chronicfluoxetinetreat- PhilosTransRSocLondBBiolSci,2012,367, mentinmiddle-agedratsinduceschangesintheexpres- 2485–2494. sionofplasticity-relatedmoleculesandinneurogenesis. 31. McEwenBS:Stressandhippocampalplasticity.Annu BMCNeurosci,2012,13,5–13. RevNeurosci,1999,22,105–122. 18. HinkleCL,DiestelS,LiebermanJ,ManessPF:Metallo- 32. McEwenBS,ChattarjiS,DiamondDM,JayTM, protease-inducedectodomainsheddingofneuralcellad- ReaganLP,SvenningssonP,FuchsE:Theneurobiologi- hesionmolecule(NCAM).JNeurobiol,2006,66, calpropertiesoftianeptine(Stablon):frommonoamine 1378–1395. hypothesistoglutamatergicmodulation.MolPsychiatry, 19. HombergJR,OlivierJD,BlomT,ArentsenT,vanBrun- 2010,15,237–249. schot,SchipperP,Korte-BouwsGetal.:Fluoxetineex- 33. MiettinenR,HajszanT,RiedelA,Szigeti-BuckK, ertsage-dependenteffectsonbehaviorandamygdala LeranthC:Estimationofthetotalnumberofhippocam- neuroplasticityintherat.PLoSOne,2011,6,e16646. palCA1pyramidalneurons:newmethodologyapplied 20. JaakoK,Aonurm-HelmA,KaldaA,AnierK, tohelplessrats.JNeurosciMethods,2012,205, ZharkovskyT,ShastinD,ZharkovskyA:Repeatedcita- 130–138. lopramadministrationcounteractskainicacid-induced 34. NacherJ,GuiradoR,Castillo-GomezE:Structuralplas- spreadingofPSA-NCAM-immunoreactivecellsandloss ticityofinterneuronsintheadultbrain:roleof ofreelinintheadultmousehippocampus.EurJPharma- PSA-NCAMandimplicationsforpsychiatricdisorders. col,2011,666,61–71. NeurochemRes,2013,38,1122–1133.

Pharmacological Reports, 2013, 65, 1471–1478 1477 35. NowackaM,ObuchowiczE:BDNFandVEGFin expressionofplasticity-relatedproteinsinthehippocam- thepathogenesisofstress-inducedaffectivediseases: pusandmedialprefrontalcortexoftherat.Neurosci- Aninsightfromexperimentalstudies.PharmacolRep, ence,2007,144,368–374. 2013,65,535–546. 42. TurnerCA,WatsonSJ,AkilH:Thefibroblastgrowth 36. OtaKT,DumanRS:Environmentalandpharmacological factorfamily:ofaffectivebehavior. modulationsofcellularplasticity:Roleinthepatho- ,2012,76,160–174. physiologyandtreatmentofdepression.NeurobiolDis, 43. VareaE,Blasco-IbanezJM,Gomez-ClimentMA, 2013,57,28–37. Castillo-GomezE,CrespoC,Martinez-GuijarroFJ, 37. Pillai-NairN,PanickerAK,RodriguizRM,GilmoreKL, NácherJ:Chronicfluoxetinetreatmentincreasestheex- DemyanenkoGP,HuangJZ,WetselWC,ManessPF: pressionofPSA-NCAMinthemedialprefrontalcortex. Neuralcelladhesionmolecule-secretingtransgenicmice Neuropsychopharmacology,2007,32,803–812. displayabnormalitiesinGABAergicinterneuronsandal- 44. VareaE,GuiradoR,Gilabert-JuanJ,MartiU,Castillo- terationsinbehavior.JNeurosci,2005,25,4659–4671. GomezE,Blasco-IbanezJM,CrespoC,NacherJ: 38. PoltorakM,FryeMA,WrightR,HemperlyJJ,George ExpressionofPSA-NCAMandsynapticproteinsinthe MS,PazzagliaPJ,JerrelsSA etal.:Increasedneuralcell amygdalaofpsychiatricdisorderpatients.JPsychiatr adhesionmoleculeintheCSFofpatientswithmooddis- Res,2012,46,189–197. order.JNeurochem,1996,66,1532–1538. 45. VawterMP,FryeMA,HemperlyJJ,VanderPuttenDM, 39. PompiliM,SerafiniG,InnamoratiM,VenturiniP, UsenN,DohertyP,SaffellJL etal.:Elevatedconcentra- Fusar-PoliP,SherL,AmoreM,GirardiP:Agomelatine, tionofN-CAMVASEisoformsinschizophrenia.JPsy- anovelintriguingantidepressantoptionenhancingneu- chiatrRes,2000,34,25–34. roplasticity:A criticalreview.WorldJBiolPsychiatry, 2013,14,412–431. 40. RadleyJJ,MorrisonJH:Repeatedstressandstructural plasticityinthebrainAgeingResRev,2005,4,271–287. 41. SairanenM,O’LearyOF,KnuuttilaJE,CastrenE: Received: August 26, 2013; in the revised form: September 18, 2013; Chronicantidepressanttreatmentselectivelyincreases accepted: September 20, 2013.

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