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

Overview

Journal Front Neural Circuits

Date 2018 Sep 14

PMID 30210305

Citations 26

Authors

Maria Papathanou

Meaghan Creed

Matthijs C Dorst

Zisis Bimpisidis

Sylvie Dumas

Hanna Pettersson

Camilla Bellone

Gilad Silberberg

Christian Luscher

Asa Wallen-Mackenzie

Affiliations

Soon will be listed here.

Abstract

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.

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References

Joyce M, Rayport S . Mesoaccumbens dopamine neuron synapses reconstructed in vitro are glutamatergic. Neuroscience. 2000; 99(3):445-56. DOI: 10.1016/s0306-4522(00)00219-0. View

Lammel S, Steinberg E, Foldy C, Wall N, Beier K, Luo L . Diversity of transgenic mouse models for selective targeting of midbrain dopamine neurons. Neuron. 2015; 85(2):429-38. PMC: 5037114. DOI: 10.1016/j.neuron.2014.12.036. View

Takamori S, Rhee J, Rosenmund C, Jahn R . Identification of differentiation-associated brain-specific phosphate transporter as a second vesicular glutamate transporter (VGLUT2). J Neurosci. 2001; 21(22):RC182. PMC: 6762262. View

Chuhma N, Zhang H, Masson J, Zhuang X, Sulzer D, Hen R . Dopamine neurons mediate a fast excitatory signal via their glutamatergic synapses. J Neurosci. 2004; 24(4):972-81. PMC: 6729804. DOI: 10.1523/JNEUROSCI.4317-03.2004. View

Birgner C, Nordenankar K, Lundblad M, Mendez J, Smith C, Le Greves M . VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation. Proc Natl Acad Sci U S A. 2009; 107(1):389-94. PMC: 2806710. DOI: 10.1073/pnas.0910986107. View

Hnasko T, Chuhma N, Zhang H, Goh G, Sulzer D, Palmiter R . Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo. Neuron. 2010; 65(5):643-56. PMC: 2846457. DOI: 10.1016/j.neuron.2010.02.012. View

Moss J, Ungless M, Bolam J . Dopaminergic axons in different divisions of the adult rat striatal complex do not express vesicular glutamate transporters. Eur J Neurosci. 2011; 33(7):1205-11. DOI: 10.1111/j.1460-9568.2011.07594.x. View

Pascoli V, Terrier J, Espallergues J, Valjent E, OConnor E, Luscher C . Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature. 2014; 509(7501):459-64. DOI: 10.1038/nature13257. View

El Mestikawy S, Wallen-Mackenzie A, Fortin G, Descarries L, Trudeau L . From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci. 2011; 12(4):204-16. DOI: 10.1038/nrn2969. View

10.

Ekstrand M, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E . Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A. 2007; 104(4):1325-30. PMC: 1783140. DOI: 10.1073/pnas.0605208103. View

11.

Stuber G, Hnasko T, Britt J, Edwards R, Bonci A . Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate. J Neurosci. 2010; 30(24):8229-33. PMC: 2918390. DOI: 10.1523/JNEUROSCI.1754-10.2010. View

12.

Li X, Qi J, Yamaguchi T, Wang H, Morales M . Heterogeneous composition of dopamine neurons of the rat A10 region: molecular evidence for diverse signaling properties. Brain Struct Funct. 2012; 218(5):1159-76. DOI: 10.1007/s00429-012-0452-z. View

13.

Wallen-Mackenzie A, Gezelius H, Thoby-Brisson M, Nygard A, Enjin A, Fujiyama F . Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation. J Neurosci. 2006; 26(47):12294-307. PMC: 6675433. DOI: 10.1523/JNEUROSCI.3855-06.2006. View

14.

Yamaguchi T, Qi J, Wang H, Zhang S, Morales M . Glutamatergic and dopaminergic neurons in the mouse ventral tegmental area. Eur J Neurosci. 2015; 41(6):760-72. PMC: 4363208. DOI: 10.1111/ejn.12818. View

15.

Fortin G, Bourque M, Mendez J, Leo D, Nordenankar K, Birgner C . Glutamate corelease promotes growth and survival of midbrain dopamine neurons. J Neurosci. 2012; 32(48):17477-91. PMC: 6621856. DOI: 10.1523/JNEUROSCI.1939-12.2012. View

16.

Yamaguchi T, Wang H, Morales M . Glutamate neurons in the substantia nigra compacta and retrorubral field. Eur J Neurosci. 2013; 38(11):3602-10. PMC: 3903463. DOI: 10.1111/ejn.12359. View

17.

Yamaguchi T, Sheen W, Morales M . Glutamatergic neurons are present in the rat ventral tegmental area. Eur J Neurosci. 2007; 25(1):106-18. PMC: 3209508. DOI: 10.1111/j.1460-9568.2006.05263.x. View

18.

Fremeau Jr R, Troyer M, Pahner I, Nygaard G, Tran C, Reimer R . The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron. 2001; 31(2):247-60. DOI: 10.1016/s0896-6273(01)00344-0. View

19.

Luscher C . The Emergence of a Circuit Model for Addiction. Annu Rev Neurosci. 2016; 39:257-76. DOI: 10.1146/annurev-neuro-070815-013920. View

20.

Mameli M, Halbout B, Creton C, Engblom D, Parkitna J, Spanagel R . Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc. Nat Neurosci. 2009; 12(8):1036-41. DOI: 10.1038/nn.2367. View