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

Abstract

Expression of the Vglut2/Slc17a6 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 Vglut2 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.

Audiogenic Seizures in theFmr1Knock-Out Mouse Are Induced byFmr1Deletion in Subcortical, VGlut2-Expressing Excitatory Neurons and Require Deletion in the Inferior Colliculus

“…Serotonergic and cholinergic neurons have been reported to release glutamate, but VGlut3 is the transporter in these neurons (Higley et al, 2011;Wang et al, 2019). There is a small subpopulation of dopaminergic neurons in the ventral tegmental area that express VGlut2, so we cannot rule out the possibility that they play a role in AGSs (Papathanou et al, 2018). Finally, Fmr1 deletion in the auditory system periphery does not play a role since auditory hair cells did not express Cre in our vGlut2 Cre/ϩ experiments and since AGS induction was unaffected in the vGlut1 Cre/ϩ experiments, even though spiral ganglion cells expressed Cre.…”

Roles of dopamine and glutamate co‐release in the nucleus accumbens in mediating the actions of drugs of abuse

“…In summary, the discovery of DA/glutamate co-releasing neurons within the last two decades has opened up a wide range of speculation of these cells' possible roles, from reward and SUDs [15,21,41,97,120] to DA neuron degeneration and Parkinson's disease [84][85][86][87]. Research has established that the majority of these cotransmitting neurons project to the mNAcSh, where DA release is modulated by drugs of abuse.…”

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

“…In addition to dopamine neurons, there is a rich heterogeneity of glutamate and GABA neurons in the different anatomical subdomains of the VTA, and neurotransmitter co-release (e.g. dopamineglutamate, GABA-glutamate, GABA-dopamine) from VTA neurons is common 23,[29][30][31] .…”