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

Neurons in the ventral tegmental area (VTA) that project to the lateral habenula (LHb) are unique in their ability to release both the inhibitory neurotransmitter GABA and the excitatory neurotransmitter glutamate. While this GABA-glutamate (VTAGG) corelease is a known phenomenon, its functional significance in reward circuitry has been ambiguous. This study demonstrates that VTAGG neurotransmission is not fixed in its effect; rather, it acts as a state-dependent switch, where the postsynaptic membrane potential of the LHb neuron dictates the net effect of the signal.

Using an intersectional genetic approach to target VTA neurons that co-express vesicular GABA (VGAT) and glutamate (VGLUT2) transporters, the researchers optogenetically stimulated these terminals in the LHb. They performed ex vivo electrophysiology to observe how postsynaptic currents changed across varying membrane potentials. To test the behavioral consequences, they combined optogenetics with chemogenetics (DREADDs) to artificially manipulate the activity state (hyperpolarization vs. depolarization) of LHb neurons while measuring reward-seeking behavior (self-stimulation).

• State-Dependent Switching: The researchers found that LHb neurons respond to VTAGG input with either excitation or inhibition depending on their resting potential. Hyperpolarized cells exhibit net excitation, while more depolarized cells exhibit net inhibition.
• Reinforcement Mechanism: In standard conditions, VTAGG inputs drive net inhibition in the LHb, which promotes positive reinforcement. Crucially, this reward-seeking behavior depends on GABA, but not glutamate, release.
• Motivational Valence: By using chemogenetic receptors to bias the LHb state, the authors showed they could reverse the behavioral outcome. Hyperpolarizing the LHb shifted the VTAGG effect toward excitation and abolished the reinforcing effect of the input, while depolarization enhanced the inhibitory effect and the subsequent reward-seeking behavior.