Multi-transmitter neurons in the mammalian central nervous system

The traditional view of neural communication often assigns a single, primary neurotransmitter to a specific neuron type. This paper argues that this simplification overlooks the significant functional diversity present in the mammalian central nervous system. Many neurons release multiple small-molecule neurotransmitters, such as GABA, glutamate, dopamine, and acetylcholine, in varying combinations. Recognizing these multi-transmitter profiles is essential for correctly interpreting neural connectivity and the dynamic ways neurons influence their downstream targets.

The paper highlights four specific categories of multi-transmitter neurons to illustrate the complexity of these signaling arrangements:

• GABA and Glutamate: Neurons in the entopeduncular nucleus (EP) co-release these transmitters to the lateral habenula. Evidence suggests they can be packaged into the same synaptic vesicles, allowing for simultaneous release that may sharpen excitatory signaling or serve as a mechanism for gain control.
• Dopamine and GABA/Glutamate: Midbrain dopamine neurons are known to release GABA in the striatum. Notably, they lack standard GABA-synthesizing enzymes, instead acquiring GABA through plasma membrane transport or non-canonical synthesis pathways, potentially using VMAT2 as a vesicular transporter. Some neurons also co-release glutamate, likely from distinct axonal microdomains.
• VIP and Acetylcholine: Cortical interneurons expressing VIP and choline acetyltransferase (ChAT) appear to be a distinct subclass of GABAergic neurons. Current research suggests they can influence both excitatory pyramidal neurons and neighboring interneurons, potentially using GABA and acetylcholine to target different cells.

Identifying that neurons release multiple transmitters fundamentally changes how we view brain circuits. Rather than static, one-way channels, these synapses act as dynamic nodes where information processing can be modulated independently by different transmitters. This complexity is likely regulated by activity, context, and even developmental stages. As connectomics and circuit mapping research progresses, researchers must move beyond single-transmitter markers to fully appreciate the "neurochemical signature" of individual neurons and how these diverse signals coordinate complex behaviors, reward learning, and plasticity.