Bocchio Chiavetto, L.

Cattaneo, A

Gennarelli, M

Maffioletti, E

Maina, Giuseppe

Rosso, Gianluca

Tardito, D

Zanardini, R

English

Institutional Research Information System University of Turin

S374 P.2.a. Mood disorders and treatment − Affective disorders (basic)provided the strongest evidence of an association with sexual dys-function following antidepressant treatment. However, our resultsare likely due to chance and there was no strong supporting evi-dence in our replication cohort. The lack of biological plausibilityin the identified genes also reduces confidence in our findings. Theinclusion of an interaction term in our regression model allowedus to identify genetic variants whose association with sexualdysfunction differed by antidepressant (SSRI or NARI), which areclinically important, but also increased our chances of obtainingspurious associations. Larger, randomised controlled trials arerequired before pharmacogenetics may be able to guide clinicalpractice in reducing antidepressant-induced sexual dysfunction.References[1] Perlis, R.H., et al., 2009. Genetic and Clinical Predictors of SexualDysfunction in Citalopram-Treated Depressed Patients. Neuropsycho-pharmacology. 34(7): p. 1819–1828.[2] Adkins, D.E., et al., 2012. Genome-wide pharmacogenomic study ofcitalopram-induced side effects in STAR*D. Translational Psychiatry.[3] Strohmaier J., et al., 2011. Sexual dysfunction during treatment withserotonergic and noradrenergic antidepressants: clinical description andthe role of the 5-HTTLPR. World J Biol Psychiatry, Oct; 12(7): 528−38.P.2.a.022 Robust efficacy of 3b-methoxy-pregnenolone(MAP4343) in validated animal models ofdepression suggests a new antidepressantmechanismN. Froger1 °, L. Parésys1, V. Fournet1, N. Ladurelle1, J. Cottin1,J. Leandri1, K. Hoffmann2, E. Fuchs2, M. Bianchi1, I. Villey1,E.E. Baulieu1 1MAPREG SAS, Le Kremlin Bicêtre, France;2German Primate Center, Clinical Neurobiology Laboratory37077, Göttingen, GermanyDepressive disorders (DDs) are common psychiatric disordersworldwide whose pathophysiology is linked to an alteration ofcentral monoaminergic systems. In particular, reduction of sero-tonergic metabolism was evoked in depressed patients and mostcurrent antidepressant drugs are selective serotonin/noradrenalinereuptake inhibitors, such as fluoxetine. However the clinical ef-ficacy of these drugs is restricted to a chronic administration,about half of target patients remain partial or non-respondersand these compounds display substantial adverse side effects,responsible for discontinuation of treatment. Accumulating evi-dences have suggested that such psychiatric disorders are closelyassociated with abnormalities in brain microtubule function. Sincelast decade, we have developed various neurosteroids that targetthe microtubular system. Accordingly, we have proposed thatneurosteroids, acting on the cytoskeleton, may constitute a neworiginal therapeutic approach for DDs. Hence, we found that the3b-Methoxy-pregnenolone (MAP4343), a derivative compound ofpregnenolone, displays a very interesting and unique antidepres-sant activity.We investigated the antidepressant effects of MAP4343 in twovalidated animal models of DDs consisting in (i) the Wistar Kyoto(WKY) rats, a spontaneous model which is known to be resistantto classic antidepressants, and (ii) the tree-shrews subjected topsychosocial stress which is considered as a non-human primatemodel. These animals received either acute (4 days in KWY rats)or chronic (4 wks in three shrews) administration of MAP4343.We assessed in KWY rats the ‘depressive-like’ behavior usingthe forced-swimming (FST) test and the ‘anxious-like’ behaviorusing the open-field. In tree-shrew, locomotor activity (LMA) andavoidance behavior were videotaped, while various physiologicalparameters known to be disturbed in DDs (sleep activity, core bodytemperature and hormone secretion) were measured. Finally, ex-pressions of a-tubulin isoforms (tyrosinated versus detyrosinated)were measured in hippocampus from these two models, therebythe infrared Western-blot technique, and the ratio tyrosinatedTubulin/detyrosinated Tubulin (Tyr/Glu-Tub ratio) was taken asindex of microtubular dynamics.When compared to vehicle-treated WKY rats, we found thatacute administration of MAP4343 (10mg/kg/day, s.c.) signifi-cantly reduced the immobility in FST (−39%, p< 0.01, n = 8)whereas fluoxetine displayed an inverse effect. MAP4343 wasable to increase the LMA in open-field arena (+56%, p< 0.001,n = 8), while fluoxetine had no effect. In tree-shrews, chronic oraladministration of MAP4343 (50mg/Kg/day, per os) significantlyreversed stress-induced LMA reduction and stress-elicited avoid-ance behavior. In addition, MAP4343 can prevent stress-inducedhypothermia, sleep disturbances and noradrenaline hypersecretion.Finally, a reduced Tyr/Glu-Tub ratio was found in these twomodels showing an alteration of microtubular dynamics in DDs.However, this alteration was not prevented by MAP43, suggestingthat MAP43 does not directly act at the level of microtubularassembly.Taken together, these data display a robust and potent antide-pressant effect of MAP4343 compound, evidenced under bothacute and chronic administration, in two validated models ofdepression from two species. Relevant antidepressant effects weredemonstrated here on translational (both behavioral and phys-iological) parameters, known to be disturbed in DDs. Furtherinvestigations, using more accurate techniques, are in progressto elucidate the cellular mechanism of action of MAP4343, inparticular on microtubular dynamics.Disclosure statement: Supported by MAPREG SAS.P.2.a.023 Common and specific blood microRNAalterations in unipolar and bipolar depressionE. Maffioletti1 °, A. Cattaneo2, R. Zanardini2, G. Rosso3,D. Tardito4, M. Gennarelli1, G. Maina3, L. Bocchio-Chiavetto21University of Brescia, Department of Molecular andTranslational Medicine, Brescia, Italy; 2IRCCS Centro SanGiovanni di Dio Fatebenefratelli, NeuropsychopharmacologyUnit, Brescia, Italy; 3Università di Torino, SCDU PsichiatriaAOU San Luigi Gonzaga, Torino, Italy; 4Università degliStudi di Milano, Dipartimento di Scienze Farmacologiche eBiomolecolari, Milano, ItalyMicroRNAs (miRNAs) are small non-coding RNAs (20−22 nu-cleotides) which regulate protein synthesis post-transcriptionallyby base-pairing to target mRNAs. Generally, miRNAs inhibitprotein synthesis either by repressing translation or by inducingdeadenylation and degradation of target mRNAs, and they arepredicted to regulate more than 50% of all the protein-codinggenes. It has been reported that almost 50% of all the sofar identified miRNAs are expressed in the human brain, withputative target genes regulating synaptogenesis and other basicneuronal processes. A role for miRNAs in neurogenesis, neuronaldifferentiation and survival, as well as in neuroplasticity, is nowwell established. Moreover, recent studies suggest that miRNAsmay be involved in the pathophysiology of neuropsychiatric dis-orders and in the action of psychotropic drugs [1]. Alterations inP.2.a. Mood disorders and treatment − Affective disorders (basic) S375miRNA expression have been observed, among others, in majordepression (MD) and bipolar disorder (BD), and their modulationhas been described after treatments with antidepressant [3] andmood stabilizer drugs. In particular, intriguing findings concernthe identification of disease- and treatment-associated miRNAsignatures in patients’ peripheral tissues, such as blood; this mayprovide further insights into the etiopathogenesis of MD andBD and contribute to identify new biomarkers for diagnosticassessment improvement and treatment personalization.Thus, the aim of this study was to investigate miRNA ex-pression levels in the blood of 20 MD and 20 BD patients,compared to 20 healthy controls. All the patients were in adepressive state [Hamilton Depression Rating Scale (HAMD)score 15] and drug-free from antidepressants; BD patientswere in treatment with mood stabilizers. Total RNA was ex-tracted from 2.5mL of peripheral blood with the PAXGeneBlood miRNA Kit (Qiagen) and analyzed with the GeneChipmiRNA 3.0 Arrays (Affymetrix), which cover all the 1733 ma-ture miRNAs and 1658 pre-miRNAs annotated in miRBase (on-line miRNA database, http://www.mirbase.org) version 17 (April2011). Data were then analyzed with Partek Genomics Suitesoftware, and the most significant results were confirmed byreal-time PCR using the TaqMan MicroRNA Assays (AppliedBiosystems). Five miRNAs were detected as differentially ex-pressed only in MD patients, 5 only in BD patients, while3 miRNAs were commonly modulated in MD and BD pa-tients. A pathway analysis, which works by identifying the tar-get genes of selected miRNAs, was performed with the on-line tool DIANA-miRPath (http://diana.imis.athena-innovation.gr/DianaTools/index.php?r=mirpath/index) and revealed the presenceof common altered pathways in MD and BD, such as long-term potentiation and depression, axon guidance, ErbB, TGF-beta,mTOR, Wnt, PI3K-Akt and neurotrophin signaling pathways,and the specific involvement of dopaminergic and glutamatergicsynapse pathways for BD.These results highlight a dysregulation in the expression ofspecific blood miRNAs in patients suffering from mood disordersand suggest putative specific alterations in the regulation ofgenes related to the dopaminergic and glutamatergic systems inBD patients.References[1] Maffioletti E., Tardito D., Gennarelli M., Bocchio-Chiavetto L. (2014).Micro spies from the brain to the periphery: new clues from studies onmicroRNAs in neuropsychiatric disorders. Front Cell Neurosci. 8, 75.doi: 10.3389/fncel.2014.00075. eCollection 2014. Review.[2] Rong H., Liu T.B., Yang K.J., Yang H.C., Wu D.H., Liao C.P., Hong F.,Yang H.Z., Wan F., Ye X.Y., Xu D., Zhang X., Chao C.A., Shen Q.J.(2011). MicroRNA-134 plasma levels before and after treatment forbipolar mania. J Psychiatr Res. 45(1), 92−5. doi: 10.1016/j.jpsychires.2010.04.028.[3] Bocchio-Chiavetto L., Maffioletti E., Bettinsoli P., Giovannini C., Big-notti S., Tardito D., Corrada D., Milanesi L., Gennarelli M. (2013).Blood microRNA changes in depressed patients during antidepressanttreatment. Eur Neuropsychopharmacol. 23(7), 602−11. doi: 10.1016/j.euroneuro.2012.06.013.P.2.a.024 Regulation of HDAC5 and Sirt2 by chronicstress and imipramine treatment in theprefrontal cortexM.M. Erburu1, J. Dominguez1, I. Muñoz-Cobo1, E. Puerta1,R.M. Tordera1 ° 1University of Navarra, Department ofPharmacology and Toxicology, Pamplona, SpainEpigenetic mechanisms mediate stable functional changes in brainplasticity in response to environmental stimuli. Among them,stress-mediated changes in histone acetylation, regulated by thesuperfamily of histone deacetylases (HDAC’s), could contribute tothe pathogenesis of depression. Likewise, antidepressant therapymight counteract these effects [1,2].Emerging clinical interest in the mechanisms that link exposureto stressful situations to the perpetuation of depressive disordersand/or increased vulnerability to relapse has stimulated the studyof mouse specific models from a longitudinal perspective, aimingto identify stable neuroadaptations induced by stress. The chronicsocial defeat stress (CSDS) model has its theoretical rationale inthe induction of ‘social subordination’ caused by short periods ofstruggle with a dominant animal followed by fellowship in an ady-acent cage. CSDS induces long-lasting anhedonia, a core symptomof clinical depression, but also anxiety and social avoidance.Interestingly, some of these behaviours are effectively reversedor prevented by different monoaminergic antidepressants [3].We hypothesise that the long-term behavioural deficits inducedby CSDS could be related to neuroadaptive changes in areassuch as the prefrontal cortex, which, is compromised in depressedpatients. Using the chronic social defeat stress (CSDS) model ofdepression we aimed to study the HDAC’s regulation by stressand imipramine treatment in the prefrontal cortex (PFC), theirfunctional implications and relevance to depression.Methods: Mice were exposed to CSDS (10 days) followedby saline or imipramine (10mg/kg/day, 4 weeks). The PFC wasobtained 24 h after the last drug administration and hdac’s mRNAwas studied and compared to human studies using the TaqManLow Density Arrays (TLDA) microfluidic card technology. Theprotein expression of selected HDAC’s, histone acetylation andother synaptic plasticity markers was explored by western-blot.Further, the effect of repeated treatment with specific HDAC’sinhibitors in histone acetylation and the expression of synapticplasticity markers were also explored.Results: While CSDS increased hdac5 and sirt2 mRNA,repeated imipramine downregulated mRNA of these enzymes.However, HDAC5 protein and its phosphorylated cytoplasmicform (p-HDAC5) were strikingly upregulated by imipramine.Sirt2 protein was oppositely regulated by stress and imipramine.Moreover, imipramine-induced Sirt2 inhibition correlated withincreased acetylated a-tubulin, the Sirt2 cytoplasmic sub-strate. Subsequently, while CSDS decreased acetylated his-tone 3 and CREB levels, imipramine induced an increase ofboth acetylated histone 3 and 4 as well as pro-BDNF andCREB.Further, both the class II HDAC inhibitor MC1568 (25mg/kg, 3weeks) and the sirt2 inhibitor 33i (1mg/kg, three weeks) elevatedacetylation levels of histone 4 and increased expression of pro-BDNF and CREB.Conclusion: Our results suggest a role for HDAC5 and Sirt2in stress-induced neuronal adaptations and in the mechanism ofaction of imipramine treatment, by which, it might stimulate theexpression of specific genes involved in synaptic plasticity.

Common and specific blood microRNA alterations in unipolar and bipolar depression

https://iris.unito.it/bitstream/2318/1590672/1/microRNA%20poster%202014%20ecnp.pdf

Common and specific blood microRNA alterations in unipolar and bipolar depression

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