The Journal of Undergraduate Neuroscience Education (JUNE), Spring 2021, 19(2):R28-R30 AMAZING PAPERS IN NEUROSCIENCE Getting Graded: Teaching Principles of Chemical Synaptic Transmission Without Action Potentials Laura Strathern School of Psychology and Neuroscience, University of St Andrews, St Andrews, UK KY16 9JP. The study of synaptic transmission is foundational for depolarizations in presynaptic neurons. This was one of the undergraduate neuroscience students. Chemical synaptic first papers to clearly demonstrate that both graded and transmitter release is usually presented as evoked by action spike-mediated chemical synaptic transmission could occur potentials, but it can also be caused by subthreshold, concurrently at an identified synapse. Discussion of this ‘graded’ changes in presynaptic membrane potential. In a work in undergraduate classrooms can encourage students 1980 publication in the Proceedings of the National to think in greater depth about the diversity of transmission Academy of Sciences, Graubard and colleagues measured mechanisms available to neurons. synaptic activity in the crustacean stomatogastric ganglion; they found that postsynaptic voltage changes occur in Key words: action potential; graded chemical synaptic response to both action potentials and to graded transmission; stomatogastric ganglion; electrophysiology Chemical synaptic transmission between neurons requires Therefore, teaching this type of synaptic transmission to the release of neurotransmitter molecules from a undergraduate neuroscience students can expand presynaptic neuron into a synaptic cleft. Once released, understanding of the diversity of synaptic transmission neurotransmitters bind to receptors on the membranes of mechanisms. postsynaptic neurons. Action-potential-evoked release is common within the nervous system. In this mode, an action RESEARCH SUMMARY potential is generated and travels along the axon to the Graubard et al. (1980) used intracellular recordings of the presynaptic terminal. At the presynaptic terminal, it causes motor neurons of the pyloric network, a central pattern a brief depolarization, which results in the opening of generator network that is part of the crustacean voltage-gated calcium channels. The resulting influx of stomatogastric ganglion. In this network, a triphasic motor calcium into the presynaptic terminal triggers fusion of pattern is generated by synaptic connections (Marder and neurotransmitter vesicles to the presynaptic membrane so Bucher, 2007) between a single pacemaker interneuron that neurotransmitter can be released (Siegel and Sapru, (anterior burster, AB) and three motor neurons (pyloric, PY; 2015). lateral pyloric, LP; and pyloric dilator, PD). Graded chemical synaptic transmission is an alternative Graubard et al. (1980) demonstrated that at chemical mode in which transmitter release is dependent on inhibitory synapses in the pyloric network of the lobster presynaptic membrane fluctuations, even when an action stomatogastric ganglion, the same neurons that release potential does not occur in the presynaptic neuron. In 1980, neurotransmitter in response to action potentials also do so Graubard, Raper and Hartline published a paper in the in response to subthreshold, graded voltages. They showed Proceedings of The National Academy of Sciences that was that both mechanisms of release could happen together and part of the early work using electrophysiology techniques to occurred as part of the standard communication between explore graded chemical synaptic transmission in the the network neurons. They compared two recordings of stomatogastric ganglion of the lobster, Panulirus interruptus. depolarization in a presynaptic neuron and resulting The paper offers a unique opportunity for educators, as it inhibitory postsynaptic potentials (IPSPs) in a postsynaptic demonstrates graded chemical synaptic transmission in neuron. For both recordings, the experimenters used the direct comparison to the action-potential-evoked same depolarizing presynaptic current, which hovered near transmission that occurs between the same neurons, so the threshold of action potential generation, sometimes students gain an understanding of how to measure both eliciting an action potential and other times not. Comparison types of chemical synaptic transmission. of the presynaptic recordings show the same initial In comparison to action-potential-evoked transmission, depolarization, resulting in identical IPSPs. After a which is taught in detail to undergraduate neuroscience maintained depolarization, one presynaptic recording students, graded chemical synaptic transmission is often not showed a small action potential occurring, while the other thoroughly discussed as a pervasive mechanism. Graded did not. The corresponding postsynaptic recording showed synaptic transmission is common in a variety of neural a small increase in the IPSP amplitude occurring at the time networks, including the retina (Werblin and Dowling, 1969), of the presynaptic spike, not seen in the other recording the crustacean stomatogastric ganglion (Graubard et al., where there was no presynaptic spike. The IPSP amplitude 1980), and the olfactory bulb (Castro and Urban, 2009). increase was clearly seen in response to the action JUNE is a publication of Faculty for Undergraduate Neuroscience (FUN) www.funjournal.org Strathern Teaching Principles of Chemical Synaptic Transmission without Action Potentials R29 potential, while the initial IPSP was in response to the evoked and graded transmission, but graded synaptic graded neurotransmitter release that occurred before the transmission is the only means of transmission at chemical action potential. These recordings showed that although a synapses for rod and cone photoreceptors in the retina presynaptic action potential evoked a response in the (Siegel and Sapru, 2015). These photoreceptors are postsynaptic neuron, the graded depolarizations of the primary sensory neurons that signal onto bipolar cells. presynaptic cell actually resulted in a larger Neuroscience textbooks such as Essential Neuroscience hyperpolarization in the postsynaptic cell than the action (Siegel and Sapru, 2015) can be used to facilitate discussion potential did. on how the cells of the retina compare to those of the Results from further recordings also showed that stomatogastric ganglion. This textbook describes the neurotransmitter was being released from the presynaptic response of rods and cones to light as graded membrane neuron even at relatively hyperpolarized ‘resting’ membrane responses, and that their release of glutamate is constant in potential (-55mV). This observation has important the absence of light. Reading Graubard et al. (1980) gives implications; it means that information is being transmitted more depth to this explanation. Stomatogastric ganglion at these types of synapses over a wide range of presynaptic cells, like the cells in the retina, are continuously releasing voltages, which in turn enables fine tuning of postsynaptic neurotransmitter due to voltage fluctuations, except when responses. hyperpolarized. However, while neurons of the stomatogastric ganglion have neurites that are both VALUE presynaptic and postsynaptic, the photoreceptors of the Graubard et al. (1980) provides an introduction for retina absorb light at their outer segments and release undergraduate neuroscience students to a more detailed neurotransmitter from their axon terminals. Comparison of understanding of graded chemical synaptic transmission. It these two systems provides a platform for discussing is not the first paper to demonstrate graded chemical multiple aspects of synaptic transmission. synaptic transmission; however, it is short, easily Graubard et al. (1980) may also help students engage accessible, and has figures that provide a clear illustration with even earlier papers on graded synaptic transmission. of key findings. The paper also highlights the advantages of Some of the first studies to discover graded synaptic using small, well understood invertebrate neural networks. transmission in neurons include Werblin & Dowling (1969), Because the stomatogastric ganglion is a system of only who studied the retina of the vertebrate mudpuppy. roughly 30 neurons, with a defined connectome, it is an ideal Although their paper is much longer and more extensive place to study principles of basic synaptic physiology and than Graubard et al. (1980), highly motivated students could neuromodulation. Understanding these principles is critical gain further insight from Werblin and Dowling (1969) into as they fundamentally govern how neurons communicate how graded synaptic transmission was first discovered in with one another. the vertebrate retina. At the conclusion of their paper, Graubard et al. (1980) Graded transmission is sometimes thought of as less discuss the neuronal qualities that support graded common than action-potential-evoked transmission, but this transmission at chemical synapses. They argue that key may not be the case. Roberts and Bush, in their 1981 book features are: 1) closely situated sites for input and output; Neurones Without Impulses provide a compilation of early and 2) a transmitter release threshold that is suitably work showing how common this type of signaling is in different from the threshold for action-potential-evoked nervous systems. Examples of graded synaptic transmission. In their study, each neurite was both receiving transmission continue to be documented in more recent and