By Seul Ah Kim

Normal brain function requires proper synaptic communication between neurons, through a specific match between release molecules (neurotransmitters) and their corresponding detectors (postsynaptic receptors). Interestingly, there are parts of the brain where neurons simultaneously release opposing neurotransmitters, glutamate and GABA, that excite and inhibit postsynaptic cells, respectively.

Recently, scientists have been debating the precise functional organization of glutamate and GABA co-release. Are these neurotransmitters co-packaged in individual vesicles, or independently packaged in segregated pools of vesicles? Knowing whether opposing transmitters are co-packaged is crucial for understanding the rules for synaptic integration and driving the activity pattern of the lateral habenula (LHb). The LHb is involved in reward, aversion, stress, and cognitive function and is implicated disorders associated with mood and substance use like major depression, schizophrenia, and cocaine addiction. Moreover, it is a strong modulator of downstream dopamine- and serotonin-releasing neurons. Due to the challenges involved with monitoring two neurotransmitters released at the same time and repeatedly examining single vesicle release from the same synapse, until recently the mechanism of glutamate/GABA co-release remained unclear.

In our current study, we developed a new method combining computational modeling with experimental and analytical approaches to measure neurotransmitter release from individual presynaptic terminals repeatedly and examined the statistics of these signals. We discovered that glutamate and GABA are co-packaged in the same vesicles, suggesting that release at these synapses results in synchronously evoked excitatory and inhibitory signals in LHb.

Potential modes of glutamate and GABA co-release from individual synaptic terminals in which the neurotransmitters are co-packaged and released together in the same vesicle (left) or each class of vesicle is released independently (right).

Considered together with previous research showing that shifts in the ratio of glutamate and GABA released onto the LHb underlies circuit dysregulation associated with psychiatric disorders, our results suggest that the synaptic changes associated with these disorders may occur at a vesicular level.

Seul Ah Kim is a graduate student in the lab of Bernardo Sabatini at Harvard Medical School.

Learn more in the original research article:
Co-packaging of opposing neurotransmitters in individual synaptic vesicles in the central nervous system. Kim SA, Wallace ML, El-Rifai M, Knudsen AR, Sabatini BL. Neuron. 2022 Feb 3. https://doi.org/10.1016/j.neuron.2022.01.00