9/27/16 – W4D2H4 Synaptic Transmission

Why This Topic? Action potentials are the basic unit of signaling in the central nervous system (CNS). Neurons are complex organs (computers?) that receive signals from many other neurons; summation of excitation and inhibition by postsynaptic neurons permits a neuron to integrate the electrical information provided by all synapses acting on it at any given moment. There are many clinical applications for understanding synapse physiology including: several targets for psychiatric drugs molecular basis of memory formation toxin effects on synaptic machinery.

Learning Objectives 1. Compare excitatory and inhibitory neurotransmitters and identify the major examples of each neurotransmitter type in the CNS. 2. Compare ionotropic and metabotropic receptors. 3. Describe how neurotransmitter is released at chemical synapses, including the role of calcium. 4. Describe the mechanism by which neurotransmitter is cleared at chemical synapses. 5. Outline the key differences between chemical and electrical synapses. 6. Describe how temporal and spatial summation of synaptic potentials affect postsynaptic responses. Reading: Preston & Wilson. Lippincott’s Illustrated Reviews: Physiology, North American ed. Wolters Kluwer/Lippincott publisher, 2013, pp. 53-64.

LO #1: Compare excitatory and inhibitory neurotransmitters and identify the major examples of each neurotransmitter type in the CNS. Basic anatomy and terminology: Can you identify the presynaptic and postsynaptic cell?

LO #1: Compare excitatory and inhibitory neurotransmitters … LO #1: Compare excitatory and inhibitory neurotransmitters …. (continued) Don’t be confused by the convention for inward and outward currents. The important thing is to understand the change in the membrane potential! Depolarization is excitatory and hyperpolarization is inhibitory. By convention current ALWAYS is described as the movement of positive charge. – even if only negative ions are moving! Say what? EPSC = excitatory post synaptic current EPSP = excitatory post synaptic potential

LO #1: Compare excitatory and inhibitory neurotransmitters … LO #1: Compare excitatory and inhibitory neurotransmitters …. (continued) Excitatory postsynaptic potentials (EPSPs): depolarizing or excitatory postsynaptic potentials are generated by opening of non-selective cation channels. Current through these channels has a reversal potential of 0 mV. Opening of these channels produces an inward current, and depolarizes the cell. Inhibitory postsynaptic potentials (IPSPs): hyperpolarizing or inhibitory postsynaptic potentials are generated by increases in K+ or Cl- permeability. Opening these channels will produce an outward current (either outward K+ or inward Cl- flow) and hyperpolarize the cell.

LO #1: Compare excitatory and inhibitory neurotransmitters … LO #1: Compare excitatory and inhibitory neurotransmitters …. (continued) Based on your reading, what do you think is the difference between a fast and slow synaptic potential?

LO #1: Compare excitatory and inhibitory neurotransmitters … LO #1: Compare excitatory and inhibitory neurotransmitters …. (continued)

LO #1: Compare excitatory and inhibitory neurotransmitters … LO #1: Compare excitatory and inhibitory neurotransmitters …. (continued) Enhancement to better appreciate the potential benefit and complexity of these reflexes

LO #1: Compare excitatory and inhibitory neurotransmitters … LO #1: Compare excitatory and inhibitory neurotransmitters …. (continued) Enhancement to better appreciate the potential benefit and complexity of these reflexes

LO #2: Compare ionotropic and metabotropic receptors. Fast synaptic potentials: the transmitter binds to and activates receptors that also function as ion channels – these are referred to as ionotropic receptors (1–20 ms in duration, e.g., nicotinic AChR in skeletal muscle). Recovery of the potential by receptor desensitization (inactivation) and clearance of released transmitter. Desensitization occurs when receptor closes even though transmitter is still bound. Transmitter clearance is achieved at most chemical synapses when the released transmitter is cleared by transporters, but also can be by degradation (e.g., ACh by acetylcholinesterase) Transporters located on glial cells near the synapse can play a central role in CNS. Uptake transporters use secondary active transport driven by Na+ gradients. Several therapeutic drugs target these transporters.

LO #2: Compare ionotropic and metabotropic receptors. Slow synaptic potentials: the transmitter binds to and activates a G-protein complex receptor (GPCRs, e.g., muscarinic AChR in cardiac muscle) – a.k.a metabotropic. This causes a conductance change via activation of a G-protein cascade. Typical durations are several to many seconds. The conductance change can persist well after the transmitter has been removed. The duration is determined by the time to shut off the activated G-protein signaling components — the time for the G-protein to hydrolyze GTP to GDP and the time for the GPCR itself to be desensitized.

LO #3: Describe how neurotransmitter is released at chemical synapses, including the role of calcium. Have we seen these before?

4. Describe the mechanism by which neurotransmitter is cleared at chemical synapses.

4. Describe the mechanism by which neurotransmitter is cleared at chemical synapses.

LO #4. Describe the mechanism by which neurotransmitter is cleared … (continued)

At this point, you have a good understanding of chemical synapses. LO #5. Outline the key differences between chemical and electrical synapses. At this point, you have a good understanding of chemical synapses. Electrical synapses are gap junctions. Did you watch the two movies on Canvas? (see Pre-Class Optional: Synaptic Integration and Electrical Synapses)

LO #5. Outline the key differences between chemical and electrical synapses (continued). Gap junctions provide a non-selective conductance path between the two cells, passing ions and second messengers. Because this current is non-selective, the reversal potential for the current is 0 mV. No current flows when the two cells are at the same voltage. This property makes electrical synapses particularly good at synchronizing the electrical activity in populations of cells. Cardiac muscle and smooth muscle contract synchronously Many cardiac diseases are marked by a disruption of normal patterns of gap junctions between the cells.

LO #5. Outline the key differences between chemical and electrical synapses (continued). This figure from the syllabus illustrates the concept of having a reversal potential of 0 mV.

LO #5. Outline the key differences between chemical and electrical synapses (continued). This figure is from the videos and syllabus and illustrates how a dye can spread among all of these retinal cells via gap junctions. If there were no gap junctions, only the cell that was injected with yellow die would glow yellow and the rest of the field of retinal cells would not be visible.

LO #6. Describe how temporal and spatial summation of synaptic potentials affect postsynaptic responses (continued). Synaptic integration is the process by which an individual neuron processes its synaptic inputs and converts them into an output signal. This involves two levels of integration. Summation of EPSPs and IPSPs Neuronal circuitry (This is a bit beyond LO #6, so we’ll just look at some pictures!)

LO #6. Describe how temporal and spatial summation of synaptic potentials affect postsynaptic responses (continued). Temporal And Spatial Summation A typical central nervous system (CNS) neuron can receive input from several thousand presynaptic neurons (a phenomenon called convergence) and can send its output to several thousand post synaptic neurons (a phenomenon called divergence). In the CNS, inputs from presynaptic neurons are spread across the dendrites of the post synaptic neuron. Dendrites exhibit a remarkable range of structures depending on the precise function of the cell. Because the amplitude of a single synaptic input is typically less than 1 mV, activity of many inputs must be summed or “integrated” to depolarize a post synaptic neuron to its threshold so it can generate action potentials.

LO #6. Describe how temporal and spatial summation of synaptic potentials affect postsynaptic responses (continued).

LO #6. Describe how temporal and spatial summation of synaptic potentials affect postsynaptic responses (continued). The real deal

LO #6. Describe how temporal and spatial summation of synaptic potentials affect postsynaptic responses (continued). From your syllabus

Can you describe post-synaptic inhibition? LO #6. Describe how temporal and spatial summation of synaptic potentials affect postsynaptic responses (continued). Can you describe post-synaptic inhibition? Post-synaptic inhibition: A form of spatial integration: IPSPs generated by inhibitory inputs to a neuron can cancel EPSPs on the dendrites or at the soma. The average of all the EPSPs received by the cell are balanced against the average of all the IPSPs. Appropriate stimuli can disrupt this cancellation and cause small differences in either the EPSPs or the IPSPs to dominate. Thus, firing patterns of many neurons in the brain reflect changes in the balance of an ongoing barrage of excitatory and inhibitory synaptic inputs

LO #6. types of pre-synaptic and post-synaptic inhibition. The blue multipolar neuron can be EITHER the “post-synaptic” cell OR the “pre-synaptic” cell and the target cells are the post-synaptic cells.

Can you describe pre-synaptic inhibition? LO #6. Describe how temporal and spatial summation of synaptic potentials affect post-synaptic responses (continued). Can you describe pre-synaptic inhibition? Pre-synaptic inhibition: Activation of IPSPs made on the presynaptic terminal that reduces the amount of transmitter released by that pre-synaptic terminal. A common mode of action is that the released inhibitory transmitter activates GPCRs, which initiate a G-protein cascade that inhibits presynaptic Ca2+ channels and hence fewer Ca2+ channels open when the terminal is depolarized (see Figure 8 in your syllabus).

LO #6. Describe how temporal and spatial summation of synaptic potentials affect postsynaptic responses (continued). In this example in your syllabus, the yellow neuron is an inhibitory neuron. Therefore, if you inhibit an inhibitory neuron (using pre-synaptic inhibition, your get LESS inhibition of the purple post-synaptic cell! Get it?

LO #6. types of pre-synaptic and post-synaptic inhibition. The blue multipolar neuron can be EITHER the “post-synaptic” cell OR the “pre-synaptic” cell and the target cells are the post-synaptic cells.

AMPA and NMDA receptors - fast EPSPs that also use second messengers AMPA and NMDA receptors - fast EPSPs that also use second messengers! Enhancing a response.