Dopamine Neurons That Cotransmit Glutamate, From Synapses to Circuits to Behavior.

Daniel Eskenazi,Stephen Rayport,Samira Ztaou,Vlad Velicu,Lauren Malave,Nao Chuhma,Susana Mingote,Leora Yetnikoff

doi:10.3389/fncir.2021.665386

Abstract

Discovered just over 20 years ago, dopamine neurons have the ability to cotransmit both dopamine and glutamate. Yet, the functional roles of dopamine neuron glutamate cotransmission and their implications for therapeutic use are just emerging. This review article encompasses the current body of evidence investigating the functions of dopamine neurons of the ventral midbrain that cotransmit glutamate. Since its discovery in dopamine neuron cultures, further work in vivo confirmed dopamine neuron glutamate cotransmission across species. From there, growing interest has led to research related to neural functioning including roles in synaptic signaling, development, and behavior. Functional connectome mapping reveals robust connections in multiple forebrain regions to various cell types, most notably to cholinergic interneurons in both the medial shell of the nucleus accumbens and the lateral dorsal striatum. Glutamate markers in dopamine neurons reach peak levels during embryonic development and increase in response to various toxins, suggesting dopamine neuron glutamate cotransmission may serve neuroprotective roles. Findings from behavioral analyses reveal prominent roles for dopamine neuron glutamate cotransmission in responses to psychostimulants, in positive valence and cognitive systems and for subtle roles in negative valence systems. Insight into dopamine neuron glutamate cotransmission informs the pathophysiology of neuropsychiatric disorders such as addiction, schizophrenia and Parkinson Disease, with therapeutic implications.

Highlights

Dopamine (DA) neurons were first identified by their monoamine content, and by the expression of the DA synthetic enzyme tyrosine hydroxylase (TH)
This review focuses on DA neuron GLU cotransmission and addresses the key questions: (1) Where do DA-GLU neurons project? (2) Are DA and GLU released together or separately? (3) What are the synaptic functions of DA neuron GLU cotransmission? (4) What are the developmental roles of DA neuron GLU cotransmission? (5) How are DA-GLU neurons affected by DA neuron toxins? (6) What are the behavioral roles
But not the basolateral amygdala (BLA) (Mingote et al, 2015a). Most of these studies have been performed on brain slices from juvenile mice; future studies on mice in early life or late adulthood may differ since the proportion of DA neurons expressing vesicular glutamate transporter 2 (VGluT2) may change with age

Summary

INTRODUCTION

Dopamine (DA) neurons were first identified by their monoamine content, and by the expression of the DA synthetic enzyme tyrosine hydroxylase (TH) (for review see Iversen and Iversen, 2007). Lack of DA neuron GLU cotransmission in DATCre;VGluT2flox/flox cKO mice disrupts this loop; it reduces DA release in the striatum, in line with disrupted vesicular synergy (Stuber et al, 2010; Alsiö et al, 2011). Expression of DA receptors was increased in both the dorsal and ventral striatum in DATCre;VGluT2flox/flox cKO mice, further suggesting a role for DA neuron GLU cotransmission in the establishment of meso-striatal projections (Alsiö et al, 2011). Disruption of DA neuron GLU cotransmission in DATCre;VGluT2flox/flox cKO mice blunts acute responses to psychostimulants (Birgner et al, 2010; Hnasko et al, 2010; Fortin et al, 2012; Steinkellner et al, 2018). DATIRES−Cre;VGluT2flox/flox cKO mice showed reduced progressive intracranial optogenetic self-stimulation of VTA TH+ neurons, supporting the hypothesis that DA neuron GLU cotransmission regulates the magnitude of operant behaviors (Wang et al, 2017).

Method

Findings

CONCLUSION