VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety.
Three different subtypes of H(+)-dependent carriers (named VGLUT1-3) concentrate glutamate into synaptic vesicles before its exocytotic release. Neurons using other neurotransmitter than glutamate (such as cholinergic striatal interneurons and 5-HT neurons) express VGLUT3. It was recently reported that VGLUT3 increases acetylcholine vesicular filling, thereby, stimulating cholinergic transmission. This new regulatory mechanism is herein designated as vesicular-filling synergy (or vesicular synergy). In the present report, we found that deletion of VGLUT3 increased several anxiety-related behaviors in adult and in newborn mice as early as 8 d after birth. This precocious involvement of a vesicular glutamate transporter in anxiety led us to examine the underlying functional implications of VGLUT3 in 5-HT neurons. On one hand, VGLUT3 deletion caused a significant decrease of 5-HT(1A)-mediated neurotransmission in raphe nuclei. On the other hand, VGLUT3 positively modulated 5-HT transmission of a specific subset of 5-HT terminals from the hippocampus and the cerebral cortex. VGLUT3- and VMAT2-positive serotonergic fibers show little or no 5-HT reuptake transporter. These results unravel the existence of a novel subset of 5-HT terminals in limbic areas that might play a crucial role in anxiety-like behaviors. In summary, VGLUT3 accelerates 5-HT transmission at the level of specific 5-HT terminals and can exert an inhibitory control at the raphe level. Furthermore, our results suggest that the loss of VGLUT3 expression leads to anxiety-associated behaviors and should be considered as a potential new target for the treatment of this disorder.
Amilhon
Bénédicte
B
Inserm, U952, Université Pierre et Marie Curie (UPMC), 75005 Paris, France.
Lepicard
Eve
E
Renoir
Thibault
T
Mongeau
Raymond
R
Popa
Daniela
D
Poirel
Odile
O
Miot
Stéphanie
S
Gras
Christelle
C
Gardier
Alain M
AM
Gallego
Jorge
J
Hamon
Michel
M
Lanfumey
Laurence
L
Gasnier
Bruno
B
Giros
Bruno
B
El Mestikawy
Salah
S
D026922:Amino Acid Transport Systems, Acidic / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology*; D017660:Autoreceptors / Q000502:physiology; D002540:Cerebral Cortex / Q000503:physiopathology; D006624:Hippocampus / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D017729:Presynaptic Terminals / Q000378:metabolism; D011903:Raphe Nuclei / Q000503:physiopathology; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D009435:Synaptic Transmission; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D026922:Amino Acid Transport Systems, Acidic; D017660:Autoreceptors; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C493453:Slc18a2 protein, mouse; C504941:Slc17a8 protein, mouse