Journal Article

Targeting VGLUT2 in Mature Dopamine Neurons Decreases Mesoaccumbal Glutamatergic Transmission and Identifies a Role for Glutamate Co-release in Synaptic Plasticity by Increasing Baseline AMPA/NMDA Ratio

Creed, Meaghan, Pettersson, Hanna, Silberberg, Gilad, Wallén-Mackenzie, Åsa, Bimpisidis, Zisis, Dumas, Sylvie, Papathanou, Maria, Bellone, Camilla, Lüscher, Christian, Dorst, Matthijs C.

2018

Overview

Expression of the gene encoding the Vesicular glutamate transporter 2 (VGLUT2) in midbrain dopamine (DA) neurons enables these neurons to co-release glutamate in the nucleus accumbens (NAc), a feature of putative importance to drug addiction. For example, it has been shown that conditional deletion of gene expression within developing DA neurons in mice causes altered locomotor sensitization to addictive drugs, such as amphetamine and cocaine, in adulthood. Alterations in DA neurotransmission in the mesoaccumbal pathway has been proposed to contribute to these behavioral alterations but the underlying molecular mechanism remains largely elusive. Repeated exposure to cocaine is known to cause lasting adaptations of excitatory synaptic transmission onto medium spiny neurons (MSNs) in the NAc, but the putative contribution of VGLUT2-mediated glutamate co-release from the mesoaccumbal projection has never been investigated. In this study, we implemented a tamoxifen-inducible Cre-LoxP strategy to selectively probe VGLUT2 in mature DA neurons of adult mice. Optogenetics-coupled patch clamp analysis in the NAc demonstrated a significant reduction of glutamatergic neurotransmission, whilst behavioral analysis revealed a normal locomotor sensitization to amphetamine and cocaine. When investigating if the reduced level of glutamate co-release from DA neurons caused a detectable post-synaptic effect on MSNs, patch clamp analysis identified an enhanced baseline AMPA/NMDA ratio in DA receptor subtype 1 (DRD1)-expressing accumbal MSNs which occluded the effect of cocaine on synaptic transmission. We conclude that VGLUT2 in mature DA neurons actively contributes to glutamatergic neurotransmission in the NAc, a finding which for the first time highlights VGLUT2-mediated glutamate co-release in the complex mechanisms of synaptic plasticity in drug addiction.

• Publisher: Frontiers Research Foundation,Frontiers Media S.A
• Subject: Adaptations / addiction / Addictions / alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism / amphetamine / Amphetamine - pharmacology / Amphetamines / Animals / Behavior, Animal - drug effects / Behavioral plasticity / Cocaine / Cocaine - pharmacology / Disease Models, Animal / Dopamine / Dopamine Agents - pharmacology / Dopamine D1 receptors / Dopaminergic Neurons - metabolism / Drug abuse / Drug addiction / Gene deletion / Gene expression / Genetics / Glutamatergic transmission / Glutamic Acid - metabolism / Glutamic acid receptors (ionotropic) / Glutamic acid transporter / Information processing / medium spiny neurons / Mesencephalon / Mice / Mice, Transgenic / N-Methyl-D-aspartic acid receptors / N-Methylaspartate - metabolism / Neuronal Plasticity - drug effects / Neuronal Plasticity - physiology / Neurons / Neuroscience / Neurosciences / Neurotransmission / Nucleus accumbens / Nucleus Accumbens - metabolism / Nucleus Accumbens - physiology / Optics / Optogenetics / Patch-Clamp Techniques / Receptors, Dopamine D1 - metabolism / Rodents / Spiny neurons / striatum / substance use disorder / substance use disorders / Substance-Related Disorders - metabolism / Synaptic plasticity / Synaptic transmission / Synaptic Transmission - drug effects / Synaptic Transmission - physiology / Tamoxifen / ventral tegmental area / ventral tegmental area (VTA) / Ventral Tegmental Area - metabolism / Vesicular Glutamate Transport Protein 2 - metabolism / α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid