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Ethanol blocks a novel form of iLTD, but not iLTP of inhibitory inputs to VTA GABA neurons

Neuropsychopharmacology volume 48, pages 1396–1408 (2023)Cite this article

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Abstract

The ventral tegmental area (VTA) is an essential component of the mesocorticolimbic dopamine (DA) circuit that processes reward and motivated behaviors. The VTA contains DA neurons essential in this process, as well as GABAergic inhibitory cells that regulate DA cell activity. In response to drug exposure, synaptic connections of the VTA circuit can be rewired via synaptic plasticity—a phenomenon thought to be responsible for the pathology of drug dependence. While synaptic plasticity to VTA DA neurons as well as prefrontal cortex to nucleus accumbens GABA neurons are well studied, VTA GABA cell plasticity, specifically inhibitory inputs to VTA GABA neurons, is less understood. Therefore, we investigated the plasticity of these inhibitory inputs. Using whole cell electrophysiology in GAD67-GFP mice to identify GABA cells, we observed that these VTA GABA cells experience either inhibitory GABAergic long-term potentiation (iLTP) or inhibitory long-term depression (iLTD) in response to a 5 Hz stimulus. Paired pulse ratios, coefficient of variance, and failure rates suggest a presynaptic mechanism for both plasticity types, where iLTP is NMDA receptor-dependent and iLTD is GABAB receptor-dependent—this being the first report of iLTD onto VTA GABA cells. As illicit drug exposure can alter VTA plasticity, we employed chronic intermittent exposure (CIE) to ethanol (EtOH) vapor in male and female mice to examine its potential impact on VTA GABA input plasticity. Chronic EtOH vapor exposure produced measurable behavioral changes illustrating dependence and concomitantly prevented previously observed iLTD, which continued in air-exposed controls, illustrating the impact of EtOH on VTA neurocircuitry and suggesting physiologic mechanisms at play in alcohol use disorder and withdrawal states. Taken together, these novel findings of unique GABAergic synapses exhibiting either iLTP or iLTD within the mesolimbic circuit, and EtOH blockade specifically of iLTD, characterize inhibitory VTA plasticity as a malleable, experience-dependent system modified by EtOH.

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Fig. 1: Inhibitory afferents to VTA GABA neurons exhibit either iLTP or iLTD in response to a 5 Hz stimulus.
Fig. 2: The iLTP and iLTD observed at the inhibitory VTA GABA synapses are unique synaptic events.
Fig. 3: The iLTP does not involve the nitric oxide pathway but is somewhat NMDAR-dependent.
Fig. 4: The iLTD is GABAB receptor-dependent, but independent of the endocannabinoid system and dopamine receptor D2.
Fig. 5: Chronic ethanol treated mice displayed anxiety and compulsive-like behavior during the ethanol withdraw period and eliminated iLTD.

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Acknowledgements

We acknowledge assistance of Calvin Smith with molecular biology studies and Andrew J Payne with EtOH studies. USPHS NIH grants R15DA038092 (JE), R15DA049260 (JE) and AA020919 (SCS/JE) supported this work. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by institutional Mentoring Grants (JE) and Graduate Fellowship Awards (TMN).

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  1. These authors contributed equally: Teresa M. Nufer, Bridget J. Wu.

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  1. Brigham Young University, Neuroscience Center, Provo, UT, 84602, USA

    Teresa M. Nufer, Zachary Boyce, Scott C. Steffensen & Jeffrey G. Edwards

  2. Brigham Young University, Department of Cell Biology and Physiology Provo, Provo, UT, 84602, USA

    Bridget J. Wu & Jeffrey G. Edwards

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TMN, BJW, and JGE designed the research and wrote the paper. TMN and BJW preformed electrophysiology experiments. ZB performed quantitative PCR experiments. SCS provided funding, resources and expertise for the project. All authors performed the studies and analyzed the data, or edited the paper, and approve the final version.

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Correspondence to Jeffrey G. Edwards.

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Nufer, T.M., Wu, B.J., Boyce, Z. et al. Ethanol blocks a novel form of iLTD, but not iLTP of inhibitory inputs to VTA GABA neurons. Neuropsychopharmacol. 48, 1396–1408 (2023). https://doi.org/10.1038/s41386-023-01554-y

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