Decoding Neurotransmitter Switching: The Road Forward

Abstract

Neurotransmitter switching is a form of brain plasticity in which an environmental stimulus causes neurons to replace one neurotransmitter with another, often resulting in changes in behavior. This raises the possibility of applying a specific environmental stimulus to induce a switch that can enhance a desirable behavior or ameliorate symptoms of a specific pathology. For example, a stimulus inducing an increase in the number of neurons expressing dopamine could treat Parkinson's disease, or one affecting the number expressing serotonin could alleviate depression. This may already be producing successful treatment outcomes without our knowing that transmitter switching is involved, with improvement of motor function through physical activity and cure of seasonal depression with phototherapy. This review presents prospects for future investigation of neurotransmitter switching, considering opportunities and challenges for future research and describing how the investigation of transmitter switching is likely to evolve with new tools, thus reshaping our understanding of both normal brain function and mental illness.

Figure 1.

Genetic reporters of transmitter switching in the adult brain. A, Glutamate to GABA is the most frequently observed switch. B, C, Strategies for genetic labeling of switching neurons. Left to right, mouse genotype, fluorescent reporters expressed before stimulation, after activation of CreER^T recombinase by tamoxifen, and after switching has been induced. B, This strategy will provide high-throughput brain-wide identification and quantification of transmitter switching. C, This strategy will yield real-time information about the kinetics of switching in relation to stimulus activity.

Figure 2.

Cascades of transmitter switching. A stimulus triggers a primary transmitter switching event in one brain region (yellow rectangle), which then induces secondary switching (green rectangles) and even tertiary switching (blue rectangles). Prevention of transmitter switching at the primary level will prevent the consequent secondary and tertiary events.

Figure 3.

Synergistic transmitter switching. Brain regions 1 and 2 respond with transmitter switching after stimulation (yellow arrows). The two regions regulate different but interdependent aspects of a complex behavior (red rectangle) to exert a synergistic effect. For example, running triggers switching in both the PPN and in the DG that leads to enhanced motor skill learning and enhanced episodic memory, respectively, which synergistically promote the chance of the escape of a mouse from a predator.

Figure 4.

Analysis of the behavioral consequence of overriding transmitter switching in a neuronal population that projects to another brain region. The GABA-to-glutamate (GAD1-to-vGluT1) switch is used as an example. Only GABAergic neurons that project to brain region A, where RG-EIAV-DIO-Flp is injected, will express Cre-dependent Flp recombinase, which then allows the expression of exogenous GAD1 or shRNA to vGluT1 to override the switch. The transmitter switch in GABAergic neurons that project to other brain regions will not be affected. NTS, neurotransmitter switch.