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The influence of CaMKII and ERK phosphorylation on BDNF changes observed in mice selectively devoid of CREB in serotonergic or noradrenergic neurons

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Abstract

Background

The transcription factor CREB and the neurotrophin BDNF are important mood regulators due to their profound role in controlling the neuronal plasticity. Our previously published results from transgenic mice functionally lacking CREB in chosen neural populations have shown that BDNF upregulation evoked by chronic treatment with fluoxetine seems to be dependent on CREB residing exclusively in serotonergic neurons. To further elucidate this observation, we focused on the representative signaling cascades engaged in the regulation of BDNF production.

Methods

The study was carried out on mice lacking CREB in noradrenergic (Creb1DBHCre) or serotonergic (Creb1(TPH2CreERT2) neurons in CREM deficient background. Animals received fluoxetine (10 mg/kg, ip) or desipramine (20 mg/kg, ip) for 21 days. The expression of following proteins and their phosphorylated forms was assessed by Western blot: CREB, BDNF, CaMKIIα, ERK1/2.

Results

We showed that consistent with previously observed BDNF upregulation, chronic treatment with fluoxetine causes an increase in the pool of active CaMKIIα in w/t males, while in Creb1TPH2CreERT2 mutants, this effect ceased along with the observed decrease in ERK1/2 phosphorylation. These effects were region- and sex-specific. We did not observe a similar pattern of changes regarding the levels of BDNF expression and the CaMKIIα, ERK1/2 kinases in Creb1DBHCre mice exposed to desipramine. However, sex-dependent changes in the regulation of CaMKIIα and ERK1/2 activity were also observed.

Conclusions

Our study highlights the pivotal role of CREB in response to antidepressants, emphasizing different sex-dependent vulnerabilities to particular drugs and the important impact of CREM on the effects of CREB deletion.

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Abbreviations

BDNF:

brain derived neurotrophic factor

BCA:

bicinchoninic acid

BSA:

bovine serum albumin

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

CREB:

cyclic AMP response element binding protein

CREM:

cyclic AMP response element modulator

DBH:

dopamine β-hydroxylase

DMI:

desipramine

ERK:

extracellular signal-regulated kinase

ER:

estrogen receptor

ERT2:

mutant estrogen ligand-binding domain

FLX:

fluoxetine

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

HIP:

hippocampus

KO:

knock out

LC:

locus coeruleus

MAP:

mitogen-activated protein kinase

PFC:

prefrontal cortex

RIPA:

radioimmunopre- cipitation assay buffer

RN:

raphe nuclei

SAL:

saline

SSRI:

selective serotonin reuptake inhibitor

TPH:

tryptophan hydroxylase-2

TrkB:

tropomyosin receptor kinase B

TST:

tail suspension test.

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Authors and Affiliations

  1. Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

    Katarzyna Rafa-Zabłocka, Grzegorz Kreiner, Monika Bagińska & Irena Nalepa

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  1. Katarzyna Rafa-Zabłocka
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  2. Grzegorz Kreiner
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  3. Monika Bagińska
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  4. Irena Nalepa
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Correspondence to Grzegorz Kreiner.

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Rafa-Zabłocka, K., Kreiner, G., Bagińska, M. et al. The influence of CaMKII and ERK phosphorylation on BDNF changes observed in mice selectively devoid of CREB in serotonergic or noradrenergic neurons. Pharmacol. Rep 71, 753–761 (2019). https://doi.org/10.1016/j.pharep.2019.04.008

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