The role of astrocytes in depression, its prevention, and treatment by targeting astroglial gliotransmitter release

Journal
Proceedings of the National Academy of Sciences
ISSN
0027-8424
Date Issued
2024
Author(s)
Yorley Duarte
Daisy Quintana-Donoso
Rodrigo Moraga-Amaro
Ivanka Dinamarca
Yordan Lemunao
Kevin Cárdenas
Tamara Bahamonde
Tabita Barrientos
Pedro Olivares
Camila Navas
Francisco J. Carvajal
Yessenia Santibánez
Raimundo Castro-Lazo
María Paz Meza
Ramon Jorquera
Gonzalo I. Gómez
Marina Henke
Rodrigo Alarcón
Laureen A. Gabriel
Susanne Schiffmann
Waldo Cerpa
Felipe Simon
Sergio Linsambarth
Fernando Gonzalez-Nilo
Jimmy Stehberg
Type
journal-article
DOI
URL
Abstract
<jats:p>The role of ventral hippocampus (vHipp) astroglial gliotransmission in depression was studied using chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) rodent models. CRS increased Cx43 hemichannel activity and extracellular glutamate levels in the vHipp and blocking astroglial Cx43 hemichannel-dependent gliotransmission during CRS prevented the development of depression and glutamate buildup. Moreover, the acute blockade of Cx43 hemichannels induced antidepressant effects in rats previously subjected to CRS or CUMS. This antidepressant effect was prevented by coinjection of glutamate and D-serine. Furthermore, Cx43 hemichannel blockade decreased postsynaptic NMDAR currents in vHipp slices in a glutamate and D-serine-dependent manner. Notably, chronic microinfusion of glutamate and D-serine, L-serine, or the NMDAR agonist NMDA, into the vHipp induced depressive-like symptoms in nonstressed rats. We also identified a small molecule, cacotheline, which blocks Cx43 hemichannels and its systemic administration induced rapid antidepressant effects, preventing stress-induced increases in astroglial Cx43 hemichannel activity and extracellular glutamate in the vHipp, without sedative or locomotor side effects. In conclusion, chronic stress increases Cx43 hemichannel-dependent release of glutamate and D-/L-serine from astrocytes in the vHipp, overactivating postsynaptic NMDARs and triggering depressive-like symptoms. This study highlights the critical role of astroglial gliotransmitter release in chronic stress-induced depression and suggests it can be used as a target for the prevention and treatment of depression.</jats:p>
Project(s)
Dataset(s)
Subjects
astrocytes

; 

cacotheline

; 

cx43 hemichannels

; 

depression

; 

tat-cx43l2

; 

animals

; 

antidepressive agents

; 

astrocytes

; 

connexin 43

; 

depression

; 

glutamic acid

; 

hippocampus

; 

male

; 

neurotransmitter agents

; 

rats

; 

rats, sprague-dawley

; 

receptors, n-methyl-d-aspartate

; 

serine

; 

stress, psychological

; 

cacotheline

; 

connexin 43

; 

fluoxetine

; 

glutamic acid

; 

ketamine

; 

neurotransmitter

; 

peptide

; 

picrotoxin

; 

racemase

; 

serine

; 

strychnine

; 

tat l2 peptide

; 

unclassified drug

; 

vortioxetine

; 

agents interacting with transmitter, hormone or drug receptors

; 

antidepressant agent

; 

connexin 43

; 

glutamic acid

; 

n methyl dextro aspartic acid receptor

; 

serine

; 

amino acid sequence

; 

amygdala

; 

animal cell

; 

animal experiment

; 

animal model

; 

article

; 

astrocyte

; 

basolateral amygdala

; 

cell viability

; 

cell viability assay

; 

chronic stress

; 

controlled study

; 

depression

; 

diagnostic test accuracy study

; 

fluorescence intensity

; 

forced swim test

; 

gap junction

; 

hela cell line

; 

hippocampus

; 

hydrogen bond

; 

immobility time

; 

immunofluorescence

; 

locomotion

; 

major depression

; 

male

; 

microglia

; 

molecular docking

; 

molecular dynamics

; 

mouse

; 

nerve cell plasticity

; 

nonhuman

; 

open field test

; 

physiological stress

; 

rat

; 

surface plasmon resonance

; 

synaptic transmission

; 

tail suspension test

; 

ventral hippocampus

; 

animal

; 

depression

; 

drug effect

; 

drug therapy

; 

hippocampus

; 

mental stress

; 

metabolism

; 

sprague dawley rat