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

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.

Expression of type I mGluRs predicts plasticity in the hippocampal stratum radiatum interneurons.

Changes in synaptic strength between hippocampal CA1 pyramidal cell synapses are partly responsible for memory acquisition. This plasticity is modulated by feedforward inhibitory interneurons in the stratum radiatum. While radiatum interneurons experience either long-term depression (LTD), short-term depression (STD), or lack plasticity, it is unclear whether plasticity correlates to specific interneuron subtypes. Using whole-cell electrophysiology and real-time quantitative PCR, we characterized the plasticity expressed by different interneuron subtypes. We first analyzed calcium binding proteins and cholecystokinin mRNA expression patterns to determine cell subtype. We then assessed endocannabinoid (eCB) biosynthetic enzyme mRNA expression, including diacylglycerol lipase α, N-acyl-phosphatidylethanolamine phospholipase D, and 12-lipoxygenase, and metabotropic glutamate receptors that often mediate plasticity. Neurons exhibiting LTD tended to co-express mRNA for at least one eCB biosynthetic enzyme and the metabotropic glutamate receptor 5 (mGluR5). Conversely, mGluR5 was not expressed by neurons exhibiting STD or no plasticity. Neurons that exhibited STD tended to express mRNA for at least one eCB biosynthetic enzyme and mGluR1, but not mGluR5. This suggests that plasticity of stratum radiatum interneurons could be predicted based on type I mGluR expression.

Glutamate Transmission to Ventral Tegmental Area GABA Neurons Is Altered by Acute and Chronic Ethanol.

BACKGROUND: Ventral tegmental area (VTA) GABA neurons have been heavily implicated in alcohol reinforcement and reward. In animals that self-administer alcohol, VTA GABA neurons exhibit increased excitability that may contribute to alcohol's rewarding effects. The present study investigated the effects of acute and chronic ethanol exposure on glutamate (GLU) synaptic transmission to VTA GABA neurons. METHODS: Whole-cell recordings of evoked, spontaneous, and miniature excitatory postsynaptic currents (eEPSCs, sEPSCs, and mEPSCs, respectively) were performed on identified GABA neurons in the VTA of GAD67-GFP+ transgenic mice. Three ethanol exposure paradigms were used: acute ethanol superfusion; a single ethanol injection; and chronic vapor exposure. RESULTS: Acute ethanol superfusion increased the frequency of EPSCs but inhibited mEPSC frequency and amplitude. During withdrawal from a single injection of ethanol, the frequency of sEPSCs was lower than saline controls. There was no difference in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/N-methyl-d-aspartate (NMDA) ratio between neurons following withdrawal from a single exposure to ethanol. However, following withdrawal from chronic ethanol, sEPSCs and mEPSCs had a greater frequency than air controls. There was no difference in AMPA/NMDA ratio following chronic ethanol. CONCLUSIONS: These results suggest that presynaptic mechanisms involving local circuit GLU neurons, and not GLU receptors, contribute to adaptations in VTA GABA neuron excitability that accrue to ethanol exposure, which may contribute to the rewarding properties of alcohol via their regulation of mesolimbic dopamine transmission.