Dowlat, D. S. | Search bioRxiv

bioRxiv2025

GABA-glutamate corelease is a mechanism for state-dependent neurotransmission

Ventral tegmental area neurons projecting to lateral habenula (LHb) corelease the main inhibitory and excitatory transmitters, GABA and glutamate (VTAGG). Yet the functional role of this synchronous signal remains unclear. We hypothesized that the sign of VTAGG action depends on postsynaptic state in LHb. Ex vivo, activating VTAGG terminals evoked excitatory and inhibitory responses in LHb that varied with postsynaptic membrane potential. In vivo, VTAGG inputs drove net inhibition and supported positive reinforcement that was dependent on GABA, but not glutamate, release. Using chemogenetics to bidirectionally modulate LHb, we found that LHb hyperpolarization shifted VTAGG effects toward excitation, abolishing positive reinforcement, whereas LHb depolarization enhanced net inhibition and positive reinforcement. Thus, the activity state of LHb neurons dictates whether GABA-glutamate corelease is functionally inhibitory or excitatory and can reverse the motivational valence of VTAGG input, supporting a homeostatic role for GABA-glutamate cotransmission with broad implications for disorders of imbalanced motivation.

neuroscience↗

bioRxiv2024

Ventral tegmental area interneurons revisited: GABA and glutamate projection neurons make local synapses

The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also contains GABA neurons that synapse locally on to dopamine neurons, synapses widely credited to a population of so-called VTA interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, and molecular markers, but such features have not been clearly described in VTA. Indeed, there is scant evidence that local and distal synapses originate from separate populations of VTA GABA neurons. In this study we tested whether several markers expressed in non-dopamine VTA neurons are selective markers of interneurons, defined as neurons that synapse locally but not distally. Challenging previous assumptions, we found that VTA neurons genetically defined by expression of parvalbumin, somatostatin, neurotensin, or mu-opioid receptor project to known VTA targets including nucleus accumbens, ventral pallidum, lateral habenula, and prefrontal cortex. Moreover, we provide evidence that VTA GABA and glutamate projection neurons make functional inhibitory or excitatory synapses locally within VTA. These findings suggest that local collaterals of VTA projection neurons could mediate functions prior attributed to VTA interneurons. This study underscores the need for a refined understanding of VTA connectivity to explain how heterogeneous VTA circuits mediate diverse functions related to reward, motivation, or addiction. Significance statementGABA neurons in VTA are key regulators of VTA dopamine neurons and considered central to the mechanisms by which opioids and other drugs of abuse can induce addiction. Conventionally, these VTA GABA neurons are considered interneurons, but GABA projection neurons are also abundant in VTA, and it is unclear if these represent separate populations. We found that several markers enriched in non-dopamine neurons of VTA, including Mu-opioid receptor, are also expressed in projection neurons, and thus are not selective interneuron markers. Moreover, we found that VTA GABA and glutamate projection neurons collateralize within VTA where they make local synapses. These data challenge the notion of a VTA interneuron that synapses only within VTA and suggest that inhibitory projection neurons can serve functions previously attributed to VTA interneurons.

neuroscience↗