BISC 307L 2nd Edition Lecture 9Current LectureSynaptic transmission in the CNSEntire surface of the neuron(purple) is covered with synapses (blue). A few thousand synaptic inputs in one nerve cell of the CNS. -Each input is quite weak. Not like NMJ. They each only have a slight effect on postsynatpic potential – the overall effect depends on integration(summation) of the large number of synapses over short period of time. -Can be both excitatory and inhibitory – there are more inhibitory inputs than excitatory. -Different nerve transmitters released by different synapses. Postsynaptic neurons create and put different receptors in its membrane. If you look at postsynaptic membranes directly opposite the input/transmitter release sites, you will find high concentrations of receptor that are specific for the transmitter. So you make many receptors and send them to the right places, concentrating them in high density. -Each transmitter can have multiple receptors. -Synapses can have ionotropic or metabotropic effects.Integration of Excitation and InhibitionLeft –lightning bolt represents the stimulus that stimulates the axon. There is a typical excitatorysynapse in the upper left that releases glutamate (the most abundant excitatory transmitter in the CNS). Glutamate binds to 2 types of receptors – in this case, it binds to AMPA-type GluR. Thebinding opens the channel which is specific for monovalent cations, of which the two most abundant are Na and K. Given that this has a normal negative resting potential when the synapse is active, the fact that Na is so far out of equilibrium creates a large driving force for inward sodium current, and that inward sodium current far exceeds the outward K current, because the outward K current is driven by a smaller driving force because the membrane potential is close to Ek. Big inward sodium current + small outward potassium current = net inward current that is depolarizing. When it flows out across the membrane capacitance, it depolarizes the cell. Shown on graph on the bottom: resting potential, then stimulation, then depolarization, decays back as transmitter gets inactivated or diffuses away. This is an excitatory postsynaptic potential because it brings the cell closer to threshold for an AP. -Think of threshold in terms of space/location around the neuron - it matter that this inward current exceeding outward current should happen? If the distribution of ion channels were even, it wouldn’t matter. But it’s not. Typically, where the axon comes off the cell body, called the first hemi-node or axon hillock, is the trigger zone. That’s the important place to depolarize – it will reach threshold first because there is a high density of VG Na channels so ithas the lowest threshold necessary to reach an AP. Also, each one input is small so it won’t reach threshold, but a bunch together can help it reach.-In the middle, there is an inhibitory synaptic input (orange) on the right that is activated. Typically, inhibitory transmitters in the CNS are glycine or GABA. They typically hyperpolarize thecell by generating an outward current through the channel, which is carried by potassium OR chloride - there are transmitter gated K channels, and transmitter gated Cl channels. If you openthe K channel, K will go out and that will hyperpolarize the cell. If you open a Cl channel,(typically Cl potential is more negative than resting), it will also generate an outward current. Outward current hyperpolarizes the cell, as it causes inward current to flow through other parts of the membrane like the axon hillock. That hyperpolarization takes the trigger zone away from threshold, making it less likely for the cell to generate an action potential.-Far right – Excitatory and inhibitory stimulated simultaneously. You will see a reduced EPSP, a small IPSP, or if things are just right you could even see nothing. It is not heading towards threshold though, and the cell has been inhibited. Looking up at the arrows – inward current that comes in through postsynaptic membrane of the excitatory synapse flows out the open ion channels in the postsynaptic membrane, which short circuits the current. This leaves less available to depolarize the parts that matter, like at the bottom of the hillock.Position Contributes to Synaptic EffectivenessThe trigger zone has a high density of High Na VG channels. 4 different synaptic inputs are shown in the diagram.-The one that forms a synapse closest to the trigger zone will overall have the highest effect on the trigger zone, and therefore on the cell. The one on the dendrite, which is the farthest away, will have the least effect, because these are local, graded signals that degrade with distance. So while the postsynaptic potential might be the same size, the effect on the trigger zone depends on where they synapse is located. So efficacy goes 1>2>3>4. -The postsynaptic membrane is not just a passive bunch of resistors and capacitors wired in parallel – they are active. The dendrites often contain VG Na, Ca, and K channels. That introduces wrinkles – in some neurons, there is a high enough density of VG Ca channels in the dendrites, but nowhere else, that there can be Ca dependent AP’s that spread through the dendrites, but not into the cell body. So the dendrite branching patterns are very complicated. -Presynaptic inhibition – an axon makes an axoaxonic synapse (synapse between axon and axon instead of axon and dendrite), and releases some transmitter, there are postsynaptic receptors which are ion channels on the postsynaptic membrane – usually this has a strongly inhibitory effect. If there are a lot of open channels here when the action potential is coming down the axon, then that current flowing ahead of the AP could spread out those open channels and not really depolarize the terminal. Less depolarization of the terminal would mean less calcium influx and transmitter release is a sensitive fourth power function of the rise of calcium concentration. Small decrease in Ca concentration could diminish transmitter release a lot. Short circuits the presynaptic action potential. This is the most powerful inhibition of all, and it occurs right at the end of the neuron.Synapses are not static. Activity dependent synaptic plasticity – functioning of synapse depends on what it was doing a little while ago. This is thought to be the basis of learning and memory. The diagram above shows different