PMID- 38199412
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240627
IS  - 1573-2517 (Electronic)
IS  - 0165-0327 (Linking)
VI  - 349
DP  - 2024 Mar 15
TI  - Maternal deprivation causes CaMKII downregulation and modulates glutamate, 
      norepinephrine and serotonin in limbic brain areas in a rat model of single 
      prolonged stress.
PG  - 286-296
LID - S0165-0327(24)00096-X [pii]
LID - 10.1016/j.jad.2024.01.087 [doi]
AB  - BACKGROUND: Early life stress is a major risk factor for later development of 
      psychiatric disorders, including post-traumatic stress disorder (PTSD). An 
      intricate relationship exists between various neurotransmitters (such as 
      glutamate, norepinephrine or serotonin), calcium/calmodulin-dependent protein 
      kinase II (CaMKII), as an important regulator of glutamatergic synaptic function, 
      and PTSD. Here, we developed a double-hit model to investigate the interaction of 
      maternal deprivation (MD) as an early life stress model and single prolonged 
      stress (SPS) as a PTSD model at the behavioral and molecular levels. METHODS: 
      Male Wistar rats exposed to these stress paradigms were subjected to a 
      comprehensive behavioral analysis. In hippocampal synaptosomes we investigated 
      neurotransmitter release and glutamate concentration. The expression of CaMKII 
      and the content of monoamines were determined in selected brain regions. 
      Brain-derived neurotrophic factor (BDNF) mRNA was quantified by radioactive in 
      situ hybridization. RESULTS: We report a distinct behavioral phenotype in the 
      double-hit group. Double-hit and SPS groups had decreased hippocampal presynaptic 
      glutamatergic function. In hippocampus, double-hit stress caused a decrease in 
      autophosphorylation of CaMKII. In prefrontal cortex, both SPS and double-hit 
      stress had a similar effect on CaMKII autophosphorylation. Double-hit stress, 
      rather than SPS, affected the norepinephrine and serotonin levels in prefrontal 
      cortex, and suppressed BDNF gene expression in prefrontal cortex and hippocampus. 
      LIMITATIONS: The study was conducted in male rats only. The affected brain 
      regions cannot be restricted to hippocampus, prefrontal cortex and amygdala. 
      CONCLUSION: Double-hit stress caused more pronounced and distinct behavioral, 
      molecular and functional changes, compared to MD or SPS alone.
CI  - Copyright (c) 2024. Published by Elsevier B.V.
FAU - Dorovic, Dorde
AU  - Dorovic D
AD  - Neuro Svenningsson, Department of Clinical Neuroscience, Karolinska Institutet, 
      171 76 Stockholm, Sweden; Institute of Anatomy "Niko Miljanic", School of 
      Medicine, University of Belgrade, Belgrade, Serbia. Electronic address: 
      djordjedjorovic90@gmail.com.
FAU - Lazarevic, Vesna
AU  - Lazarevic V
AD  - Neuro Svenningsson, Department of Clinical Neuroscience, Karolinska Institutet, 
      171 76 Stockholm, Sweden.
FAU - Arandelovic, Jovana
AU  - Arandelovic J
AD  - Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, 450 
      Vojvode Stepe St, 11000 Belgrade, Serbia.
FAU - Stevanovic, Vladimir
AU  - Stevanovic V
AD  - Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, 450 
      Vojvode Stepe St, 11000 Belgrade, Serbia.
FAU - Paslawski, Wojciech
AU  - Paslawski W
AD  - Neuro Svenningsson, Department of Clinical Neuroscience, Karolinska Institutet, 
      171 76 Stockholm, Sweden.
FAU - Zhang, Xiaoqun
AU  - Zhang X
AD  - Neuro Svenningsson, Department of Clinical Neuroscience, Karolinska Institutet, 
      171 76 Stockholm, Sweden.
FAU - Velimirovic, Milica
AU  - Velimirovic M
AD  - Institute of Clinical and Medical Biochemistry, School of Medicine, University of 
      Belgrade, Belgrade, Serbia.
FAU - Petronijevic, Natasa
AU  - Petronijevic N
AD  - Institute of Clinical and Medical Biochemistry, School of Medicine, University of 
      Belgrade, Belgrade, Serbia.
FAU - Puskas, Laslo
AU  - Puskas L
AD  - Institute of Anatomy "Niko Miljanic", School of Medicine, University of Belgrade, 
      Belgrade, Serbia.
FAU - Savic, Miroslav M
AU  - Savic MM
AD  - Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, 450 
      Vojvode Stepe St, 11000 Belgrade, Serbia.
FAU - Svenningsson, Per
AU  - Svenningsson P
AD  - Neuro Svenningsson, Department of Clinical Neuroscience, Karolinska Institutet, 
      171 76 Stockholm, Sweden.
LA  - eng
PT  - Journal Article
DEP - 20240109
PL  - Netherlands
TA  - J Affect Disord
JT  - Journal of affective disorders
JID - 7906073
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - X4W3ENH1CV (Norepinephrine)
RN  - 333DO1RDJY (Serotonin)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Male
MH  - Rats
MH  - Brain/metabolism
MH  - Brain-Derived Neurotrophic Factor/genetics/metabolism
MH  - *Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics/metabolism
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Glutamic Acid/metabolism
MH  - Hippocampus/metabolism
MH  - Maternal Deprivation
MH  - Norepinephrine
MH  - Rats, Wistar
MH  - *Serotonin/metabolism
MH  - *Stress Disorders, Post-Traumatic/genetics
OTO - NOTNLM
OT  - CaMKII
OT  - Double-hit stress
OT  - Glutamate release
OT  - Maternal deprivation
OT  - Post-traumatic stress disorder
OT  - Single prolonged stress
COIS- Declaration of competing interest The authors declare no conflict of interest.
EDAT- 2024/01/11 00:42
MHDA- 2024/02/09 00:42
CRDT- 2024/01/10 20:16
PHST- 2023/07/14 00:00 [received]
PHST- 2024/01/01 00:00 [revised]
PHST- 2024/01/04 00:00 [accepted]
PHST- 2024/02/09 00:42 [medline]
PHST- 2024/01/11 00:42 [pubmed]
PHST- 2024/01/10 20:16 [entrez]
AID - S0165-0327(24)00096-X [pii]
AID - 10.1016/j.jad.2024.01.087 [doi]
PST - ppublish
SO  - J Affect Disord. 2024 Mar 15;349:286-296. doi: 10.1016/j.jad.2024.01.087. Epub 
      2024 Jan 9.