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The role of CREB-mediated transcription in memory formation/Rolul transcriptiei mediate de CREB in formarea memoriei.

INTRODUCTION

The mammalian genome contains three structurally-related transcription factors that bind to the promoter cAMP responsive element (CRE) sites and are referred to as the CREB family: cAMP responsive element binding protein (CREB), cAMP responsive element modulator (CREM) and activating transcription factor 1 (ATF1). The sequence homology among the three members is based especially on their basic leucine zipper (bZIP) domain that mediates dimerization. The CREB gene generates three activator isoforms by alternative splicing: [alpha], [beta] and [DELTA].

Olfactory memory studies in Drosophila have shown that CREB-mediated transcription plays a crucial role in the switch from short-term (STM) to long-term memory (LTM). The induction of a transgene that expresses a dominant-negative member of the fly CREB family has specifically and completely blocked the formation of LTM in an olfactory task, whereas the induced expression of a dCREB2 activator isoform has enhanced it (Yin et al, 1994, 1995). Although these observations have led to the hypothesis that CREB represents a memory modulator, further experimental evidence indicates that CREB role in memory formation is rather controversial.

CREB role in different memory processes:

In order to analyze CREB involvement in different memory processes, transgenic mice have been derived under the control of [alpha]-calmodulin kinase II ([alpha]-CaMKII) promoter with an inducible and reversible CREB repressor (CREBZR), by fusing CREBS133A to a tamoxifen (TAM)-dependent mutant of an estrogen receptor ligand-binding domain (Kida et al, 2002).

* CREB, encoding or short-term memory, consolidation into long-term memory:

CREBZR and wild-type mice have been pretreated with the activator TAM or vehicle (VEH, peanut oil) and studied in a discrete cue (tone) and in a contextual fear conditioning task. All groups have shown similar levels of STM, as measured by the percentage of time spent freezing to the tone, but have differed in their freezing levels 24 hours after training. As proved by a post-hoc Newman-Keuls test, the CREBZR/TAM group has froze less than the other groups. Thus, the activation of CREB repressor by TAM does not impair initial encoding of STM, but LTM consolidation.

* CREB, memory storage or maintenance:

The activation of CREB repressor one day after training, without re-exposure to the training cage, has not impaired contextual fear memory; thus, CREB does not play a crucial role in the storage or maintenance of non-reactivated memory.

* CREB, memory retrieval and stability after retrieval:

CREBZR and wild-type mice that have been trained drug-free, but injected TAM six hours before re-exposure to the training context, freeze at equal levels; this result indicates that CREB-mediated transcription is not involved in memory retrieval. However, CREB seems to be particularly involved in memory stability after retrieval, as CREB repression has produced a disruption of memory 24 hours after re-exposure to the tone.

Additionally, a study using immunocytochemistry has demonstrated that re-exposure to a tone previously paired with shock induces an increase in CREB phosphorylation within the basal, lateral and central nuclei of the amygdala. Therefore, a role for CREB activation in both memory retrieval and memory re-consolidation may be suggested following retrieval (Hall et al, 2001).

CREB overexpression:

Increasing CREB levels specifically in the basolateral complex of the amygdala via injection of herpes simplex virus carrying a CREB gene has proved to significantly enhance LTM formation after massed fear conditioning training that normally induces STM, but little or no LTM. In conjunction, these facilitatory effects depend on CREB phosphorylation at Ser-133, which seems to be a crucial step in CREB activation. However, this study has shown that CREB overexpression does not change the level of LTM after spaced fear conditioning training or the level of STM after massed training (Josselyn et al, 2001).

Controversial evidence on CREB role in hippocampus-dependent memory formation:

* Hypomorphic CREB alleles:

To overcome strain-specific limitations of behavioral testing observed in previous experiments, the use of F1 hybrids of two different inbred strains has been recommended: CREB[alpha][DELTA], where [alpha] and [DELTA] isoforms are disrupted, but a third isoform [beta] is strongly up-regulated; CREBcomp, a compound strain with one [alpha][DELTA] allele and one CREBnull allele in which all CREB isoforms are disrupted (Gass et al, 1998).

The CREB gene dosage effect was demonstrated by a series of tasks, as CREBcomp, but not CREB[alpha][DELTA], mice proved to be impaired in water maze learning and fear conditioning. Therefore, CREBcomp mice showed weak deficits in task acquisition (path length) and memory retention (annulus crossings) in the six trials per day test and severe deficits in both acquisition and quadrant time in the two trials per day test. In the contextual long-term conditioning (24 hour test), CREBcomp mice have shown statistically highly significant deficits in freezing retention, while short-term retention of freezing has not been affected when tested 0.5 hour after training. However, the persisting tendency of CREBcomp mice to make wall contacts during ongoing training may suggest that mutants are impaired in platform searching strategies rather than in spatial memory.

The performance of a food preference task has revealed intact LTM for both CREB[alpha][DELTA] and CREBcomp, which showed a significant preference for the cued food compared with the non-cued food when tested 24 hours after training. In contrast, a study using CREB[alpha][DELTA] mice predominantly on a C57BL/6 background or on a F2 background of C57BL/6x129SVJ has indicated stronger deficits in the performance of contextual fear conditioning and Morris water maze tasks, in addition to an impairment in 24 hour memory for socially transmitted food preferences (Kogan et al, 1996). Such discrepancies seem to reflect differences in genetic background and hybrid vigor.

* Conditional, deletion of all CREB isoforms:

In order to clarify CREB role in hippocampus-dependent memory, hypomorphic CREB mutants have been added two conditional knock-out strains. CREBCamKCre7, with a 70-80 % forebrain-specific reduction of all CREB isoforms and CREBNesCre, with CREB complete deletion. CREBCamKCre7 mice have been generated by crossing CREBloxP/loxP mice with mutants expressing Cre-recombinase postnatally under the control of CamKII[alpha] promoter; CREBNesCre mice have been generated by crossing CREBloxP/loxP mice into mutants with a nestin (Nes)-driven Cre-recombinase transgene; CREBloxP/loxP mice have been generated by flanking CREB exon 10 with loxP sites (Balschun et al, 2003).

Morris water maze test has revealed that CREB marked reduction in the forebrain does not impair spatial memory in the probe trial, while CREB complete deletion may be associated with a subtle increase in swim path length that can be partially overcome by extended training. However, both strains have exhibited strongly increased wall hugging and impaired escape performance. Therefore, CREB mutants seem to adopt inappropriate search strategies rather than to be impaired in spatial memory. In addition, contextual fear conditioning, which is a hippocampus-dependent associative learning task, has indicated that long-term recognition memory is not affected in the two strains, as no significant alterations have been observed in freezing scores when tested 24 hours after training.

The failure to demonstrate substantial effects of CREB deletion on classical hippocampal tasks seems to be in conjunction with condition taste aversion learning, a hippocampus-independent memory test which was proved to be markedly impaired in CREBNesCre mice. These results could stand for a minor function of CREB-mediated transcription in the hippocampus.

* dCA1-KCREB transgenic line:

In order to disrupt the function of all three CREB family transcription factors, transgenic mice expressing KCREB have been generated, a dominant-negative mutant of CREB that prevents DNA binding (Pittenger et al, 2002). The fact that CREB-regulated transcription is specifically inhibited in KCREB transgenic mice was confirmed by the down-regulation of the CREB-regulated proenkephalin gene in these mice. Two transgenic lines have been selected: dCA1-KCREB, with expression in the hippocampus restricted to CA1 region of the dorsal half, according to oligonucleotide in situ hybridization, and str-KCREB, used as a control.

The Morris water maze task supports a role for CREB family transcription factors in dorsal hippocampus-dependent spatial memory. Therefore, the performance of a probe trial specific to deficits in spatial memory showed that dCA1-KCREB bitransgenic mice are impaired in quadrant preference, training location proximity or crossings. In an object recognition task, dCA1-KREB mutants exhibited normal discrimination between a novel and a familiar object one hour after familiarization, while the discrimination was proved to be significantly poor, 24 hours after training. When treated with doxycycline, which switches off transgene expression, dCA1-KCREB mice has shown normal discrimination 24 hours later. It can be concluded that these mutants have impaired LTM, but not STM.

A mouse model of Rubinstein-Taybi syndrome (RTS):

A mouse model of RTS was created by a C-terminal truncation mutation into the CREB-binding protein (CBP) gene, which is considered to act as a dominant-negative inhibitor to lead to RTS phenotypes in mice. Heterozygous CBP-deficient mice (CBP+/-) truncated CBP protein (residues 1-1084) containing the CREB-binding domain (residues 462-661). Memory acquisition, STM and LTM were investigated in four studies, as follows: the step-through-type passive avoidance test, which consists of an acquisition and a retention trial, suggested that CBP+/- mice are deficient in LTM, but not in memory acquisition; the Y-maze test showed that the CBP mutation does not affect STM; the fear conditioning test supported these results; however, according to the water maze test, the spatial memory of the mutants does not appear to be impaired (Oike et al, 1999).

CONCLUSIONS

The generation of transgenic lines has revealed a crucial role for CREB-mediated transcription in hippocampus-dependent LTM, but not in STM. In addition, transgenic manipulations have indicated that CREB is required not only for the initial consolidation of LTM, but also, for the stabilization of reactivated memory.

The analysis of CREB mutants in the cued conditioning task shows that CREB-mediated transcription is also involved in amygdala-dependent LTM. In conjunction with the lesion studies, it has been demonstrated that CREB overexpression in the amygdala facilitates LTM formation under specific training conditions.

The RTS mouse model demonstrates that CREB-CBP interaction is relevant to LTM formation, rather than to memory acquisition. As the CREB-binding domain is included in the truncated CBP, the LTM impairment might be caused by the fact that truncated CBP competitively binds CREB and inactivates it and could be associated with the mental retardation exhibited by the human patients.

The use of hypomorphic CREB mutants has indicated that up-regulation of CREB[beta] may have compensated in part for the loss of [alpha] and [DELTA] isoforms. Additionally, it is suggested that an upregulation of CREM could compensate for the progressive CREB deficiency. The hybrid vigor typical for F1 hybrids also seems to compensate for a reduction in CREB levels in a series of tasks.

ACKNOWLEDGMENTS AND DISCLOSURE

The authors declare that they have no potential conflicts of interest to disclose.

REFERENCES

(1.) Balschun D et al. Does cAMP response element-binding protein have a pivotal role in hippocampal synaptic plasticity and hippocampusdependent memory? J. Neurosci. 2003; 23(15): 6304-6314.

(2.) Gass P et al. Deficits in memory task of mice with CREB mutations depend on gene dosage. Learn. Mem. 1998; 5: 274-288.

(3.) Hall J et al. Fear memory retrieval induces CREB phosphorylation and Fos expression within the amygdala. Eur. J. Neurosci. 2001; 13(7): 1453-1458.

(4.) Josselyn SA et al. Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J. Neurosci. 2001; 21(7): 2404-2412.

(5.) Kida S et al. CREB required for the stability of new and reactivated fear memories. Nat. Neurosci. 2002; 5(4): 348-355.

(6.) Kogan JH et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr. Biol. 1996; 7: 1-11.

(7.) Oike Y et al. Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism. Hum. Mol. Genet. 1999; 8(3): 387-396.

(8.) Pittenger C et al. Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron 2002; 34: 447-462.

(9.) Silva AJ et al. CREB and memory. Annu. Rev. Neurosci. 1998; 21: 127-148.

(10.) Silva AJ. Molecular and cellular cognitive studies of the role of synaptic plasticity in memory. J. Neurobiol. 2003; 54: 224-237.

(11.) Yin JC et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 1994; 79: 49-58.

(12.) Yin JC et al. CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 1995; 81: 107-115.

Correspondence:

Liana Rada Borza

Spitalul Clinic de Psihiatrie "Socolsa" Iasi

Sos.Bucium, Nr. 36, cod 700282

Tel. 0232.430.920/int. 122

E-mail: liana_borza@hotmail.com

Date of Submission: September, 09, 2013/ Acceptance: November, 18, 2013

INTRODUCERE

Genomul de mamifer contine trei factori de transcriptie inruditi structural, care se leaga de siturile-promotor ale elementului de raspuns al AMPc (CRE) si care sunt cunoscuti drept familia CREB, respectiv: proteina de legare a elementului de raspuns al AMPc (CREB), elementul modulator de raspuns al AMPc (CREM) si factorul de transcriptie activator 1 (ATF1). Omologia de secventa a celor trei membri se bazeaza, in special, pe domeniul lor bZIP (basic leucine zipper) care mediaza dimerizarea. Gena CREB genereaza trei izoforme activatoare prin matisare alternativa: [alpha], [beta] si [DELTA].

Studiile privind memoria olfactiva la Drosophila au aratat ca transcriptia mediata de CREB joaca un rol crucial in trecerea de la memoria de scurta durata (MSD) la memoria de lunga durata (MLD). Inductia unei transgene care exprima un membru dominantnegativ al familiei CREB la muste a blocat, in mod specific si complet, formarea MLD intr-o sarcina olfactiva, in timp ce expresia indusa a unei izoforme activatoare dCREB2 a intensificat-o (Yin et al, 1994, 1995). Cu toate ca aceste observatii au condus la ipoteza conform careia CREB reprezinta un modulator al memoriei, dovezi experimentale suplimentare indica faptul ca rolul CREB in formarea memoriei este, mai degraba, unul controversat.

Rolul CREB in diferite procese de memorie:

Pentru a analiza implicarea CREB in diferite procese de memorie, s-au generat soareci transgenici sub controlul promotorului [alpha]-calmodulin kinazei II ([alpha]-CaMKII) cu un represor CREB inductibil si reversibil (CREBIR), prin fuzionarea CREBS133A cu un mutant dependent de tamoxifen (TAM) al unui domeniu de legare a ligandului specific receptorului estrogenic (Kida et al., 2002).

* CREB, codificarea sau memoria de scurta durata, consolidarea in memoria de lunga durata:

Soarecii CREBIR si wild-type au fost tratati in prealabil cu TAM activator sau vehicul (VEH, ulei de arahide) si studiati in contextul unui semnal (ton) discret si al unei probe conditionate de frica. Toate grupele de studiu au prezentat niveluri similare ale MSD, masurate de procentajul timpului pe care soarecii l-au petrecut nemiscati la auzul tonului, dar s-au diferentiat prin nivelurile lor de imobilizare 24 de ore dupa training. Potrivit unui test post-hoc Newman-Keuls, grupul CREBIR/TAM a ramas nemiscat mai putin decat celelalte grupuri. Astfel, activarea represorului CREB de catre TAM nu afecteaza codificarea initiala a MSD, ci consolidarea MLD.

* CREB, stocarea sau mentinerea memoriei:

Activarea represorului CREB la o zi dupa training, fara a expune din nou soarecii la cusca de training, nu a afectat memoria contextuala conditionata de frica; asadar, CREB nu joaca un rol crucial in stocarea sau mentinerea memoriei non-reactivate.

* CREB, refacerea memoriei si stabilitatea dupa refacere:

Soareci CREBIR si wild-type au fost antrenati fara a li se administra medicamente, cu exceptia TAM injectat cu sase ore inainte de reexpunerea la contextul trainingului, nivelurile de imobilizare fiind egale; acest rezultat indica faptul ca transcriptia mediata de CREB nu este implicata in refacerea memoriei. Cu toate acestea, CREB pare a fi implicat, in mod special, in stabilitatea memoriei dupa refacere, intrucat represiunea CREB a provocat o intrerupere de memorie timp de 24 de ore dupa reexpunerea la tonul respectiv.

In plus, un studiu bazat pe imunocitochimie a demonstrat ca reexpunerea la un ton asociat anterior cu un soc induce o crestere a fosforilarii CREB la nivelul nucleilor bazal, lateral si central ai amigdalei cerebrale. Astfel, poate fi sugerat un rol pentru activarea CREB atat in refacerea memoriei, cat si in reconsolidarea memoriei dupa refacere (Hall et al, 2001).

Supraexpresia CREB:

Cresterea nivelurilor CREB, in special in complexul bazolateral al amigdalei, prin intermediul injectarii virusului herpes simplex, purtator al unei gene CREB, s-a dovedit a stimula, in mod semnificativ, formarea MLD dupa trainingul comasat, conditionat de frica, care, in mod normal, induce MSD, dar putin sau chiar deloc MLD. In conjunctie, aceste efecte facilitatorii depind de fosforilarea CREB la Ser-133, care pare a fi un pas crucial in activarea CREB. Totusi, acest studiu a aratat ca supraexpresia CREB nu modifica nivelul MLD dupa trainingul conditionat de frica distantat sau nivelul MSD dupa trainingul comasat (Josselyn et al, 2001).

Dovezi controversate privind rolul CREB in formarea memoriei dependente de hipocamp:

* Alelele hipomorfe ale CREB:

Pentru a depasi limitarile de tulpina ale testarii comportamentale observate in experimentele anterioare, se recomanda utilizarea de hibrizi F1 de la doua linii consangvine diferite: CREB[alpha][DELTA], in care izoformele [alpha] si [DELTA] sunt scindate, insa o a treia izoforma [beta] este puternic reglata pozitiv; CREBcomp, o tulpina compusa cu o alela [alpha][DELTA] si o alela CREBnull, in care toate izoformele CREB sunt scindate (Gass et al, 1998).

Efectul dozajului genei CREB a fost demonstrat de o serie de probe, soarecii CREBcomp, insa nu si cei CREB[alpha][DELTA], acestia dovedindu-se deficitari in ceea ce priveste invatarea in cazul labirintului cu apa si conditionarea de frica. Astfel, soarecii CREBcomp au prezentat deficite usoare de insusire a comenzilor (lungimea traseului) si de retentie a memoriei (traversari inelare) la testul cu sase repetari zilnice si deficite severe legate atat de insusire, cat si de timpul petrecut in fiecare cadran, la testul cu doua repetari zilnice. In contextul conditionarii de lunga durata (testul de 24 de ore), soarecii CREBcomp au prezentat deficite inalt semnificative statistic, de retentie a imobilizarii, in timp ce retentia pe termen scurt a imobilizarii nu a fost afectata cand a fost testata la o jumatate de ora dupa training. Totusi, tendinta persistenta a soarecilor CREBcomp de a intra in contact cu peretii pe durata desfasurarii trainingului ar putea sugera ca mutantilor le sunt afectate, mai degraba, strategiile de cautare a platformei decat memoria spatiala.

Indeplinirea unei sarcini legate de preferintele alimentare a evidentiat o MLD intacta atat la CREB[alpha][DELTA], cat si la CREBcomp, care au aratat o preferinta semnificativa pentru alimentele pentru care existau indicii in comparatie cu cele nesemnalate cand au fost testati la 24 de ore dupa training. In schimb, un studiu pe soareci CREB[alpha][DELTA], predominant pe un teren C57BL/6 sau pe un teren F2 al C57BL/6x129SVJ, a indicat deficite mai mari de executie a sarcinilor legate de conditionarea contextuala de frica si a celor legate de labirintul cu apa Morris, care se adauga la afectarea memoriei de 24 ore a preferintelor alimentare transmise social (Kogan et al, 1996). Asemenea discrepante par a reflecta diferente in terenul genetic si vigoarea hibrida.

* Deletia conditionala a tuturor informelor CREB:

Pentru a clarifica rolul CREB in memoria dependenta de hipocamp, mutantilor hipomorfi ai CREB li s-au adaugat doua linii knock-out conditionale--CREBCamKCre7, cu o reducere specifica prozencefalului de 70-80 % a tuturor izoformelor CREB si CREBNesCre, cu deletia completa a CREB. Soarecii CREBCamKCre7 au fost generati prin incrucisarea soarecilor CREBloxP/loxP cu mutanti exprimand Cre-recombinaza de tip postnatal sub controlul promotorului CamKII[alpha]; soarecii CREBNesCre au fost generati prin incrucisarea soarecilor CREBloxP/loxP cu mutanti, cu o transgena Crerecombinaza stimulata de nestina (Nes); soarecii CREBloxP/loxP au fost obtinuti prin flancarea exonului 10 al CREB cu siturile loxP (Balschun et al, 2003).

Testul labirintului cu apa Morris a reliefat faptul ca reducerea marcata a CREB in prozencefal nu afecteaza memoria spatiala in trialul probei respective, in timp ce deletia completa a CREB se poate asocia cu o crestere subtila a lungimii caii parcurse inot care poate fi depasita partial prin antrenamente prelungite. Cu toate acestea, ambele tulpini/linii au prezentat un contact foarte apropiat cu peretii si o capacitate de scapare defectuoasa. Asadar, mutantii CREB par, mai degraba, sa adopte strategii de cautare inadecvate decat sa le fie afectata memoria spatiala. In plus, conditionarea contextuala de frica, care reprezinta o sarcina de invatare asociativa dependenta de hipocamp, a indicat ca memoria de recunoastere de lunga durata nu este afectata la cele doua linii ('strains'), deoarece nu s-au observat modificari semnificative ale scorurilor de imobilizare la testarea realizata la 24 de ore de la training.

Imposibilitatea de a demonstra efecte substantiale ale deletiei CREB asupra sarcinilor clasice ale hipocampului pare a fi in conjunctie cu invatarea prin aversiune conditionata fata de gust, un test de memorie independent de hipocamp care s-a dovedit a fi deosebit de defectuos la soarecii CREBNesCre. Aceste rezultate ar putea dovedi o functie minora a transcriptiei mediate de CREB in hipocamp.

* Linia transgenica dCA1-KCREB:

Pentru a perturba functia tuturor celor trei factori de transcriptie ai familiei CREB, au fost generati soareci transgenici exprimand KCREB, un mutant dominant-negativ al CREB care impiedica legarea ADN (Pittenger et al, 2002). Faptul ca transcriptia reglata de CREB este inhibata in mod specific la soarecii transgenici KCREB a fost confirmat de reglarea negativa a genei proenkefalinei reglate de CREB la acesti soareci. S-au selectat doua linii transgenice: dCA1-KCREB, cu expresia in hipocamp, limitata la regiunea CA1 a jumatatii dorsale, conform hibridizarii in situ a oligonucleotidelor, precum si str-KCREB, folosita pe post de control/martor.

Proba labirintului cu apa Morris sprijina rolul factorilor de transcriptie din familia CREB in memoria spatiala dependenta de hipocampul dorsal. Astfel, realizarea unui trial specific deficitelor de memorie spatiala a aratat ca soarecii bitransgenici dCA1-KCREB sunt afectati in ceea ce priveste preferinta pentru un cadran anume, proximitatea locului desfasurarii trainingului sau traversarile. In cadrul unei probe de recunoastere a obiectelor, mutantii dCA1-KREB au demonstrat o capacitate normala de a diferentia un obiect nou de unul familiar la o ora dupa familiarizare, pe cand aceasta capacitate de diferentiere scade semnificativ dupa 24 de ore de la training. In urma tratamentului cu doxiciclina, care intrerupe expresia transgenica, soarecii dCA1KCREB au prezentat o capacitate normala de diferentiere la 24 de ore. Putem concluziona ca MLD a acestor mutanti este afectata, nu insa si MSD.

Un model murin al sindromului Rubinstein-Taybi:

Un model murin al sindromului RubinsteinTaybi (SRT) a fost creat prin intermediul unei mutatii prin trunchiere a capatului C-terminal in cadrul genei proteinei de legare la CREB (CBP), care se considera ca actioneaza ca inhibitor dominant negativ, conducand la fenotipuri SRT la soareci. Soarecii heterozigoti cu deficienta de CBP (CBP+/-) prezinta proteina CBP trunchiata (reziduuri 1-1084), continand domeniul de legare la CREB (reziduuri 462-661). Achizitia memoriei, MSD si MLD au fost investigate in patru studii, dupa cum urmeaza: testul de evitare pasiva de tip "step-through", care consta intr-un trial de achizitie si de retentie, a sugerat ca soarecii CBP+/- sunt deficitari in ceea ce priveste MLD, dar nu si legat de achizitia memoriei; testul labirintului Y a aratat ca mutatia CBP nu afecteaza MSD; testul conditionarii de frica a sustinut aceste rezultate; totusi, conform testului labirintului cu apa, memoria spatiala a mutantilor nu pare a fi afectata (Oike/Pike et al., 1999).

CONCLUZII:

Generarea liniilor transgenice a scos in evidenta un rol crucial pentru transcriptia mediata de CREB in MLD dependenta de hipocamp, dar nu si in MSD. In plus, manipularile transgenice au indicat ca CREB este necesar nu doar pentru consolidarea initiala a MLD, ci si pentru stabilizarea memoriei reactivate.

Analiza mutantilor CREB in cadrul probei semnalului conditionat arata ca transcriptia mediata de CREB este implicata si in MLD dependenta de amigdala. In conjunctie cu studiile de leziune, s-a demonstrat ca supraexpresia CREB in amigdala faciliteaza formarea MLD in conditii specifice de training.

Modelul murin SRT demonstreaza ca interactiunea CREB-CBP este mai relevanta pentru formarea MLD, decat pentru achizitia memoriei. Intrucat domeniul de legare a CREB este inclus in CBP trunchiata, afectarea MLD ar putea fi cauzata de faptul ca CBP trunchiata se leaga intr-o maniera competitiva de CREB si o inactiveaza, putand fi asociata cu retardul mintal manifestat de pacientii umani.

Utilizarea mutantilor hipomorfi ai CREB a indicat ca reglarea pozitiva a CREB[beta] este posibil sa fi compensat partial pierderea izoformelor [alpha] si [DELTA]. In plus, se sugereaza ca o reglare pozitiva a CREM ar putea compensa deficienta progresiva de CREB. Vigoarea hibrida tipica pentru hibrizii F1 pare, de asemenea, sa compenseze reducerea nivelurilor CREB intr-o serie de probe.

Liana Rada Borza--M. D., Ph. D., Psychiatrist, private practice

Lorica Borza--M. D., Senior Psychiatrist, Clinical Psychiatric Hospital "Socola" Iasi, Romania

Constantin Borza--M. D., Ph. D., Senior Psychiatrist, Clinical Psychiatric Hospital "Socola" Iasi, Romania

Liana Rada Borza--M. D., Ph. D., Specialist Psihiatru, practica privata, Iasi, Romania

Lorica Borza--M. D., Medic Primar Psihiatru, Spitalul Clinic de Psihiatrie "Socola" Iasi, Romania

Constantin Borza--M. D., Ph. D., Medic Primar Psihiatru, Spitalul Clinic de Psihiatrie "Socola" Iasi, Romania

MULTUMIRI SI DEVOALARI

Autorii nu declara existenta vreunui conflict de interese legat de acest articol.

BIBLIOGRAFIE

(1.) Balschun, D. et al. Does cAMP response element-binding protein have a pivotal role in hippocampal synaptic plasticity and hippocampusdependent memory? J. Neurosci. 2003; 23(15): 6304-6314

(2.) Gass, P. et al. Deficits in memory task of mice with CREB mutations depend on gene dosage. Learn. Mem. 1998; 5: 274-288

(3.) Hall, J. et al. Fear memory retrieval induces CREB phosphorylation and Fos expression within the amygdala. Eur. J. Neurosci. 2001; 13(7): 1453-1458

(4.) Josselyn, S. A. et al. Long-term memory is facilitated by cAMP response element-binding protein overexpression in the amygdala. J. Neurosci. 2001; 21(7): 2404-2412

(5.) Kida, S. et al. CREB required for the stability of new and reactivatedfear memories. Nat. Neurosci. 2002; 5(4): 348-355

(6.) Kogan, J. H. et al. Spaced training induces normal long-term memory in CREB mutant mice. Curr. Biol. 1996; 7: 1-11

(7.) Oike, Y. et al. Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism. Hum. Mol. Genet. 1999; 8(3): 387-396

(8.) Pittenger, C. et al. Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron 2002; 34: 447-462

(9.) Silva, A. J. et al. CREB and memory. Annu. Rev. Neurosci. 1998; 21: 127-148

(10.) Silva, A. J. Molecular and cellular cognitive studies of the role of synaptic plasticity in memory. J. Neurobiol. 2003; 54: 224-237

(11.) Yin, J. C. et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 1994; 79: 49-58

(12.) Yin, J. C. et al. CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 1995; 81: 107-115

Corespondenta:

LIANA RADA BORZA

Spitalul Clinic de Psihiatrie "Socola" Iasi

Sos. Bucium nr. 36, cod 700282, Iasi, Romania

Tel.: +40 232 430 920/int. 122

E-mail: liana borza@hotmail.com

Primit: Septembrie, 09, 2013/ Acceptat: Noiembrie, 18, 2013
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Title Annotation:cAMP responsive element binding protein
Author:Borza, Liana Rada; Borza, Lorica; Borza, Constantin
Publication:Bulletin of Integrative Psychiatry
Article Type:Report
Date:Dec 1, 2013
Words:4429
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Next Article:From the fundamental research to the clinical applications in psychiatry/De la cercetarea fundamentala la aplicatiile clinice in psihiatrie.
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