The brain is a wonderful organ; it starts working the moment you get up in the morning and does not stop until you get into the office. Robert Frost

Tick: You know... I've heard the smarter you are, the more wrinkly your brain. And your guys' brains must be the wrinkliest. Oh, sure, ordinary Joes like me and Arthur here, maybe our brains are a little on the smooth side. But you don't have to be a genius to know that evil is bad. And good isn't.

AnnouncementsExam 3 next Tuesday, Nov. 12 at 8 pm, Exam held at WTHR 200, CL50 224 againExam will cover through slide 64 from the 11/5 lecture (pumps and transporters).New material for the final begins with ion channels No class next Tuesday morning for exam give back

Examples of each type of movement across the membraneO2 and nonpolar substances can passively diffuse across (slowly)When a channel is opened, ions flow along their electrochemical gradientGlucose entry is facilitated by a glucose transporter (Facilitated diffusion)Na-K ATPase is an exchange mechanism that uses energy to transport both ions against their concentration gradient, from [Low] to [High].

Clicker question A recent paper in the journal Science showed that the brain extracellular volume increases dramatically during sleep, permitting the clearing of potentially harmful metabolites. By what mechanism might this be achieved?Contraction of brain musclesExpansion of mitochondria during sleepUpregulation of Na+/K+ pumpDownregulation of Na+/K+ pumpClosing of aquaporin channels

The free energy of solute movement DG= 1.4 log10[Cin/Cout] for movement of a solute into a cell.

So if Cout is greater than Cin, DG is negative, because log10[Cin/Cout] will be negative.

Active transport: Na+/K+-ATPase exampleNa+out=150 mM, Na+in=15 mMK+out=5 mM, K+in=100-150 mM

These large concentration imbalances are maintained by the Na/K pump

Na/K ATPase: Hydrolyzes ATP & transport of Na and K.

3 Na+ are pumped out for each 2 K+ that come in, so the pump is electrogenic and will also create a charge difference across the membrane

http://www.youtube.com/watch?v=awz6lIss3hQ&feature=related

ION CHANNELS

Integral membrane proteins for ion transport

GATING: Channel opening/closing is regulated.

Selectivity: Only specific ion (Na+, K+, Ca++, Cl-) can pass through the channel.

KcsA Channel: Bacterial K+ ion channel

http://www.youtube.com/watch#!v=UqxzSrjzJ70&feature=related

Zagotta, 2006

What determines the selectivity of KcsA channels?Conserved residue sequence GYGVT of P segment lines selectivity filterThe double-bonded O in pore are just large enough to admit K+ and replace hydration shell of K+ (3.0 A diameter vs 2.7 A diameter for K+)Na+ ions do not interact with the pore O atoms well and cannot easily desolvate. It is more energetically favorable to remain hydrated.Each K+ stabilized by 8 O atoms, 4 above and 4 below. 4 potential binding sites, but only two occupied at any given timeHint: Not these guys

GATING MECHANISMSVoltage-gated is when the membrane potential determines whether the channel is open or closed (e.g. Na+ channel in neurons)

Ligand-gated channel is when binding of a ligand to a receptor opens the channels (e.g. glutamate, acetylcholine)

Mechano-gated is when mechanical force opens channels (e.g. hair cells in inner ear)

Eukaryotic K+ channels are very similarPore domain is formed by S5, linker and S6 membrane spanning helicesLinker forms porePositive charges in S4 act as voltage sensors and control whether open or not. Depolarization of membrane (potential becomes more positive) causes S4 to move and open the channelKv Shaker channel

General principles of biological ion channelsSelective permeabilityTriggers can change channel conformation between closed and open states Channel open time is often limited by inactivation

ION TRANSPORT: BIOENERGETICSNow must consider the concentration gradient and the voltage gradient, or the electric potential produced by an unequal balance of charges Together this is the electrochemical gradient. DG= 1.4 log10[Cin/Cout] + zF DE

At DE = Eion (equilibrium pot.), DG = 0 1.4 log10[Cin/Cout] + zF Eion = 0zF Eion = - 1.4 log10[Cin/Cout]

In millivolts, Eion=-60/z *log10[Cin/Cout] - EQBM POTENTIAL OF ION This is the Nernst equation.

Z: Valency of ionF: Faraday constantDE: Potential Diff across membrane

New NERNST EQUATION EXAMPLESIn millivolts, Eion=-(60/z )* log10[Cin/Cout]

Cl-out=180 mM, Cl-in=9 mM : ECl=?? mVNote that each 2x or 0.5x change in the Cin/Cout ratio will be a ~.3 change in the log10 (e.g. log10(10)=1, log10(20)=1.30102)

Ca++out=2 mM, Ca++in=200 nM : ECa= ?? mV

Crash Course in Brain

The GFP brainbow!Color variants created by differential expression of variants of GFP, including yellow (EYFP), cyan (mCFPm), and red (tdTomato). In this example, the colors are not cell-type specific.

Livet, Lichtenberg, and Sanes, Harvard U

Functions of the nervous systemTake in information from the outside world the senses

Take in information from the inside world state of the body + mind

Integrate information to make conscious and unconscious decisions

Homeostasis

Execute behavior

Coordinate complex actions

Adapt

Conscious thought and awareness

Coordinate maturation and growth

Emotions

Memory

What are the cellular elements that allow us to accomplish these functions?GliaMyelin Oligodendrocytes/Schwann cellsImmune function - MicrogliaBrain homeostasis and signaling - Astrocytes

Neurons

Astrocytes maintain brain homeostasis and adjust neuronal signaling over longer time scalesAstrocytes branch densely within a small volume to contact many neurons and other cells or blood vessels

Fundamental Neuroscience. Chap. 310 microns

Astrocyte functions (partial)Secrete growth factorsIon and nutrient homeostasisNeurotransmitter clearanceNeurotransmitter recyclingParticipate in the formation and maintenance of the blood-brain barrierObtain nutrients from bloodReact to inflammationRegulate neuron and synapse developmentFundamental Neuroscience. Chap. 3

Time to make the myelin!Schwann cells are in the peripheral nervous system and form a single internode between nodes of Ranvier along the axon. Many of the PNS myelinated axons are larger (e.g. lower motor neurons going to muscles)Oligodendrocytes are found in the central nervous system and can myelinate multiple neurons.

*Myelinated AxonsThey just look cool with an electron microscope

Microglia form the main part of the brains immune and inflammatory responsesLeft: Resting microglia. Middle: Activated microglia in a diseased cortex. Right: Phagocytic microgliaFundamental Neuroscience. Chap. 3

From: From Neuron to Brain, 4th Ed.Nicholls, Martin, Wallace, and FuchsAnatomical differences between neurons: number and orientation of dendrites

Neurons signal internally and to one another through electrochemical signalsIntracellular microelectrodes are used to measure changes in the cells membrane potentialNot in cellIn cellVanders Human Physiology

Intracellular recording of neuronal potentials use sharp microelectrodes or whole-cell patch electrodesIn whole-cell recording, a high resistance seal is established between the glass pipette and cell membraneThen suction is applied to break the membrane under the electrode and form a continuous electrical path between the inside of the cell and the electrodeMichael Hausser, University College London

The electrochemical gradients for Na+ and K+ in resting neuronsVanders Human Physiology

Recall the Nernst equationDEm= -60/z*log10([Ci]/[Co]) is the equilibrium (reversal) potential for a given ion

The current flow for a given ion is given by Ohms law:V= IR or V=I/g, where V is the voltage, I is the current, R is the resistance and g=1/R is the conductance, giving I=gV

Using Na+ as an example (ENa=+60 mV), the current is the sodium conductance multiplied by the difference between the membrane potential and the equilibrium potential ENa, given by INa=gNa (Vmem-ENa), where INa is the sodium current, gNa is the sodium conductance, Vmem is the membrane potential and ENa is the sodium equilibrium potential

Resting PotentialResting potential is mainly determined by Na+ and K+ conductances (and Cl- to some extent)At resting potential, current flows through leak channels, which are ion-selective channels that are always open and not voltage-dependentAt resting potential, INa+IK=0. (assume ICl=0 for simplicity)Therefore, INa=gNa (Vmem-ENa)= -IK= -gK (Vmem-EK), where Vmem is the membrane potential.

Solving for Vmem gives Vmem=(gNaENa+gKEK)/(gNa+gK)If ENa=+60 mV and EK=-90 mV and gK/gNa=5/1, Vmem= -65 mV, which is near the resting potential of many neurons

The electrochemical gradients for Na+ and K+ in resting neurons

Clicker question If the intracellular [Na+] doubles, what will happen to the sodium equilibrium potential, ENa, and the resting membrane potential, Vmem?ENa will become more positive, and Vmem will become more positive (more depolarized). ENa will become more negative, and Vmem will become more positive (more depolarized). ENa will become more positive, and Vmem will become more negative (more hyperpolarized). ENa will become more negative, and Vmem will become more negative (more hyperpolarized).

Action potential rapid, long-distance signaling mechanism for neurons along their axonsAll-or-nothing responseReversal of VmDoes not decrement in size as it travels because it is regenerated in the axonFrom: From Neuron to Brain, 4th Ed.Nicholls, Martin, Wallace, and FuchsConductances involved

1. Rising phase -- Na2. Falling phase -- KCurrent, Voltage, Action Potential!

Steps in the generation of an action potential

Voltage-dependent properties of ion channels involved in the action potential

Operation of voltage-gated Na+ and K+ channels during the action potential

Refractory period - the time during which it is not possible to generatea second action potential

Absolute refractory period - determined by complete inactivation of voltage- sensitive Na channels - no amount of depolarization can elicitregenerative response

Relative refractory period - determined by large gk relative to gna (Na channels starting to recover from inactivation) - a large depolarization can increase gna enoughto initiate the regenerative response

Action potentials generated in response to a visual stimulusVisual stimulus= slowly moving gratingFrom David McCormicks lab, Yale

In animal studies, it is also possible to record the responses of single neurons in response to sound32 Hz SAM, 2 kHz toneNeural response to sound

Propagation of action potentials Action potentials are initiated at the axon hillock, where the axon begins to extend from the cell body Successive segments of axon regenerate the action potential

Refractory period - the time during which it is not possible to generatea second action potential

Absolute refractory period - determined by complete inactivation of voltage- sensitive Na channels - no amount of depolarization can elicitregenerative response

Relative refractory period - determined by large gk relative to gna (Na channels starting to recover from inactivation) - a large depolarization can increase gna enoughto initiate the regenerative response

Charge lost across the plasma membrane limits the distance of propagation of changes in Vmem

Water flowing through hose analogy

The spatial spread of a voltage change is proportional to the ratio of rmem/rint, where rmem and rint are the membrane resistance and cytoplasmic resistancermemrint

Membrane length constant and time constantThe length constant, or space constant, l = rm/ri, where rm is the membrane resistance and ri is the cytoplasmic resistance. V(x)=Vmax e-x/l describes the magnitude of a voltage change at a distance x from a voltage change.The time constant, t = rmcm, where cm is the membrane capacitance. V(t)=Vmax e-t/t describes how quickly voltage will rise or fall over time.Most membrane time constants are in the 10s of ms range in adult mammals, though there are much faster ones in fast cells, such as those in the auditory system.

Clicker question Based on the graph below (Rin = rmem for this example), how do you predict that the space constant and time constant will change with development in these neurons?The space constant decreases and the time constant increases. The space constant decreases and the time constant decreases. The space constant increases and the time constant increases. The space constant increases and the time constant decreases. Venkataraman and Bartlett 2013

MyelinOligodendrocyte can wrap around an axon 10-160 times resulting in stacks of plasma membrane (increase diameter of axon)

1. increases rm relative to ri for the neuron (factor of 300 or more!)2. greatly reduces loss of current across neuronal plasma membrane3. increases conduction velocity4. Current flow largely restricted to the Nodes of Ranvier(Saltatory conduction)

Saltatory conductionFrom: From Neuron to Brain, 4th Ed.Nicholls, Martin, Wallace, and Fuchs Sodium and potassium channels are clustered at the nodes of Ranvier (right) in order to regenerate the action potential

IA ForsytheAt the end of the line: common synaptic arrangementsAxo-dendritic (most common)Axo-somatic

Flow of information at chemical synapses

Electrical (action potential in presynaptic cell)

Chemical (neurotransmitter in synaptic cleft)

Electrical (Change in Vm of postsynaptic cell)Synaptic junction, whats your function?

From: From Neuron to Brain, 4th Ed.Nicholls, Martin, Wallace, and FuchsChemical synapsesCytoplasm of pre- and postsynapticcells are distinctPhysical gap between cells (synapticcleft)Chemical messenger used to relayinformation from one cell to anotherSlower than electrical transmission(synaptic delay) Most common means of cell-cellcommunication in the nervous system6. Chemical transmission can amplify signals, alter sign (excitatory or inhibitory, and avoid field effects.

Neuromuscular junction

Photo 44.14 Motor end plates, mammalian skeletal muscle. LM, gold stain.

Steps in chemical synaptic transmissionPresynaptic axon terminal is depolarized by the action potential. Calcium channels in the axon terminal that are opened by depolarization through cooperative binding (Hill coefficient approximately 4).Calcium ions flow into the neuron through the open channels. Through a complex series of protein interactions triggered by calcium, synaptic vesicles fuse with the presynaptic membrane. Fusion of the vesicles causes release of neurotransmitters stored in the vesicle. Neurotransmitter molecules are released into the synaptic cleft and bind with postsynaptic receptors. For the neuromuscular junction, the neurotransmitter is acetylcholine. Binding of acetycholine causes Na channels to open in the muscle, producing a depolarization of the muscle and leading to muscle contraction.

From: From Neuron to Brain, 4th Ed.Nicholls, Martin, Wallace, and FuchsIncrease in presynaptic calciumhttp://www.youtube.com/watch?v=t3TaMU_qXMc

The cycling of membrane at the axon terminalFrom: Principles of Neural Science, 4th Ed.Kandel, Schwartz, and Jessell

Preparing vesicles to fuseVesicles move to target, often via motor-driven microtubule pathsRabs are lipid anchored G-proteins on vesicle and target membranes that impart different membrane types with specific identitiesActivated Rab-GTP recruits tethering proteins that reversibly hold vesicle near membraneDocking occurs between SNARE protein complexes, with vSNAREs for vesicles and tSNAREs for target membranesDocked vesicles are held in place by bound SNARE complexes until signaled to fuse

From: Principles of Neural Science, 4th Ed.Kandel, Schwartz, and JessellSynaptobrevin is synaptic vesicle v-SNARE, syntaxin is presynaptic terminal t-SNARESynaptobrevin and syntaxin coil and link along another t-SNARE, SNAP-25, which is not transmembrane and has two alpha helices. Altogether, 4 alpha helices form coil on each side of docked vesicleSynaptotagmin binds to vesicle and is a Ca sensor, triggering rapid fusion (~0.1 ms)Following fusion, NSF and alpha-SNAP bind to SNARE complexNSF is an ATPase that hydrolyzes ATP to uncoil the SNARE complexThe vesicle membrane can now be recycled with clathrin and refilled with neurotransmitter

Synaptic vesicle life cycle

Figure 3. Scale model of a synaptic vesicle with ~ 70% of the known vesicle proteins depicted. The membrane lipids are in yellow. Synaptobrevin,a protein important in neurotransmitter release, is shown as are the vesicular proton pump and glutamate antiporter. Image from : Molecular Biology of the Cell 5th Edition, Alberts, Johnson, Lewis, Raff, Roberts and Walter.

Synaptic vesicles contain many proteins involved in their localization, loading, and exo/endocytosis

Lalli et al., 2003Toxic tools from nature Tetanus and Botulinum toxinsTetanus toxin cleaves synaptobrevin

Botulinum toxins cleave all three SNARE proteins

At neuromuscular junction and brainNeuromodulatorsMain neurotransmitters in brainLocalactivityWidespreadactivity

Activation of synapses can lead to depolarizations or hyperpolarizations in the postsynaptic cell Excitatory postsynaptic potential (EPSP) Cell more likely to reachthreshold and fire action potential (excitatory channel reversal potential >Vthresh) Inhibitory postsynaptic potential (IPSP)

Cell is less likely to reachthreshold (excitatory channel reversal potential

Many neurons receive both excitatory and inhibitory inputs, resulting in combined IPSPs and EPSPsBartlett and Smith 1999IPSPGABAA IPSP blockedBlocking inhibition uncovers an EPSP large enough to produce two action potentials

Different cell types are then organized into neural circuitsSchematic depicts circuitry from cat/primate primary visual cortex (V1)Black neurons are projection (Glutamate), blue are interneurons (GABA)

The Simpsons neuronhttp://www.youtube.com/watch?v=ySCyFEyuYrw

The answer is E, because closing aquaporin channels to water passage would promote the shrinking of cells. Changing the Na+/K+ pump is weakly electrogenic, but is counterbalanced by leak potassium channels usually. **Gives a way to quantify the free energy associated with a concentration gradienthttp://www.youtube.com/watch?v=Z1M8s9aLe4Q*Electronegative O substitute for O in waterNa+, though positive and monovalent, has a smaller diameter, so it does not interact with the pore O atoms well and cannot easily desolvate. It is more energetically favorable to remain hydratedWhen 3 k atoms in pore, electrostatic repulsion rejects 1. No energy barrier to move between K binding sites, so can pass ions through very quickly. **Called a Shaker channel because flies with mutations shake when anesthetized with etherSelectivity believed similar mech to KcsA. Very high flux 10e7/s, almost at diffusion limit*ECl = -78 mV in this example, Eca = +120 mV**Today were going to have an overview of the way that signals are generated and propagated in the nervous system. First, lets consider some of the amazing things that the nervous system can do. http://gfp.conncoll.edu/cooluses0.htmlThe brainbow is created using cre-lox technology- http://cre.jax.org/introduction.html

*What are some of the functions of the brain and nervous system?*Today we are going to talk about how a signal is generated in one neuron and propagated to another neuron. Glia substantially outnumber neurons in many parts of the brain, and appear to be found in equal proportions in the cerebral cortex.

There are two types of cells in the nervous system: neurons and glia. Glia are responsible for maintaining homeostasis and supporting the neurons, for immune responses in the brain, and for generating myelin, which well talk about later.

Rapid intercellular signaling that forms the basis of our thought and action takes place through the connections between neurons.

Dendrites are the signal receiving portion of the neuron. Other neurons mainly contact the dendrites and cause electrical changes in the neuron. These changes are integrated in the cell body and in the initial portion of the axon, called the initial segment or axon hillock. Axons are like the wire that transmits the electrical signal to the axon terminal. Neurotransmitter is released onto the next cell from the axon terminal. Green is a membrane EGFP stain, red is intermediate filaments**The voltage difference is measured between the intracellular and extracellular sides of the membrane using a voltmeter. There are more negative charges intracellularly than extracellularly, so the measured intracellular voltage is negative. *06.12.jpgMany cells, including neurons have established a difference in the amount of electrical charge distributed between the two sides of the plasma membrane. This creates a potential difference, or voltage, across the membrane.

In neurons, this is called the resting potential, because it is the potential when there is no stimulation of the neuron.

*Recall that the electrochemical gradient to determine the direction of ion flow is given by the Gibbs free energy that combines the concentration and electrical gradients.

At equilibrium, delta G=0 and there is no net flow of ions across the membrane. Note that this does not mean that ions are not going across the membrane, but the flux in one direction is balanced by that in the other direction.

When delta G=0, the electrical and concentration gradients are balanced. Rearranging the constants gives this equation, which is called the Nernst equation. *Many cells, including neurons have established a difference in the amount of electrical charge distributed between the two sides of the plasma membrane. This creates a potential difference, or voltage, across the membrane.

In neurons, this is called the resting potential, because it is the potential when there is no stimulation of the neuron. *Approximate ratio gk/gNa = 6.35/106.12.jpgMany cells, including neurons have established a difference in the amount of electrical charge distributed between the two sides of the plasma membrane. This creates a potential difference, or voltage, across the membrane.

In neurons, this is called the resting potential, because it is the potential when there is no stimulation of the neuron.

The answer is A**Signals are propagated rapidly along the axon of a neuron via action potentials. These are large, all or none changes in membrane potential. So the action potential can be a binary type of signal that resembles digital bits. Because the membrane potential initially goes towards zero, action potentials are depolarizing.

Here is a picture of the changes in voltage inside a cell during an action potential. These electrical changes were recorded by inserting a fine glass microelectrode into a neuron and injecting current into the neuron to induce a change in voltage (i.e. Ohms law, V=IR).

The cell depolarizes relatively slowly until it reaches threshold,after which there is a rapid depolarization and then repolarization of the membrane potential. The rapid depolarization is due to an influx of Na ions, and the falling phase is due to an efflux of potassium ions. *Na ion channels are very sensitive to voltage and open rapidly and with a high probability over a small voltage range (maybe draw this). Therefore, when a small number of them are induced to open, it sets up a positive feedback that induces other Na channels to open, causing further depolarization and causing more channels to open.

The type of K channels that establish the resting potential are not voltage sensitive and are called leak channels.

Another type of K channel is voltage sensitive opens with a delay when the neuron depolarizes. Therefore, this type of K channel is called a delayed rectifier.

After the rapid depolarization, the neuron repolarizes for two reasons. First, Na channels inactivate and no longer pass Na ions. Second, the flow of K ions through the delayed rectifier channels causes a rapid repolarization of the membrane potential that often bring the membrane potential more negative than the resting potential. This is called the after-hyperpolarization, because the cell is briefly more polarized than at rest. *06.18.jpg*To reiterate, there are competing positive and negative feedback loops that serve to generate the action potential. A depolarization of the cell causes Na channels to open, which then causes more Na channels to open.

Depolarization causes K channels to open with a delay, providing negative feedback to repolarize the neuron. Repolarization also removes the inactivation block of Na channels. *The maximum rate at which neurons can generate action potentials is limited by the refractory period. After the Na channels have inactivated and the cell is still depolarized, no amount of current in the cell will generate another action potential. This is the absolute refractory period. Once the cell repolarizes and Na channels recover from inactivation, it still takes a large amount of current to generate an action potential, much larger than usual. This is the relative refractory period. *Here is an example of real action potential firing patterns in a neuron in the visual responsive portion of the cerebral cortex. An electrode recorded the intracellular electrical signals while the animal viewed a slowly moving grating of alternating light and dark bars.Response to two consecutive presentations of AM tone. Can see reproducibility in spikes, cant see synchronization easily but its there. Can see more rapid firing at the onset versus the sustained for this 750 ms sound.

Transition: Using SAM tones or SAM noise to drive IC neurons, we found that IC neurons in both young and aged used both synchrony to the modulation and changes in firing rate to signal modulation frequency and modulation depth. ***In the axon, there is a directionality in the axon potential propagation. Action potentials are initiated at the juncture between the cell body and axon, called the axon hillock, where there is a high concentration of Na channels. Then the action potential propagates away from the hillock because Na channels are located along the axon. Successive segments of the cell membrane in the axon are depolarized and continue to regenerate the action potential. The action potential does not flow back towards the cell because region that the action potential just passed through is in its refractory period. *The maximum rate at which neurons can generate action potentials is limited by the refractory period. After the Na channels have inactivated and the cell is still depolarized, no amount of current in the cell will generate another action potential. This is the absolute refractory period. Once the cell repolarizes and Na channels recover from inactivation, it still takes a large amount of current to generate an action potential, much larger than usual. This is the relative refractory period. *If the membrane depolarization passively spreads, the voltage change will diminish rapidly as one moves away from the site of depolarization. Charge is lost through the plasma membrane. It is like water flowing through a leaky hose. If there are holes in the hose, the amount of water that reaches a distant point will be greatly diminished.

There are two ways to get around this loss of current that leads to the propagation of voltage changes. One is to have dense Na and K channels, but this is energetically very expensive. A more efficient way is to plug up the leaks in the axon hose. The answer is B. **This is achieved through myelination. Myelination greatly increases the resistance of the membrane such that charge is much more likely to flow within the cytoplasm rather than across the membrane. It also decreases the capacitance of the membrane so that the membrane time constant is much faster

Glia produce a myelin sheath around the axons of all mammalian neurons that travel long distances. This also makes it possible to regenerate the action potential at much greater intervals, cutting down on the number of Na and K channels that need to be produced and maintained. Na and K channels are then concentrated at specific gaps in the myelin sheath know as the nodes of Ranvier.*Saltatory is from a Latin root saltare meaning to hopIn an action potential, the action potential spreads rapidly from one node of Ranvier to the next, which is called saltatory conduction because the action potential seems to jump from one node to the next.

Myelin is an essential component for proper brain function. For example, Multiple sclerosis is an autoimmune disease that causes demyelination of axons. This lead to visual defects (optic nerve), cognitive difficulties (CNS) in memory and problem-solving, and motor deficits in balance, coordination, and reflexes.*Now weve gotten our action potential all the way from the axon hillock to the axon terminal. Lets look at a very simplified version of what happens at the axon terminal to cause the release of neurotransmitter.

*Neurons signal to one another mainly through chemical signals rather than electrical signals. Here is a diagram of the flow of information. The electrical signal in the first (presynaptic) cell is propagated to the axon terminal. This signal is converted to a chemical signal in the form of release of neurotransmitter onto the second (postsynaptic) cell. This causes ion channels in the second cell to open and once again produces an electrical signal.*The specialized contact point between two neurons is called a synapse. There is a small gap between the two cells called the synaptic cleft. On the top is a diagram of the information flow that I just described. The cell releasing transmitter is on the presynaptic side of the synapse and the recipient cell with neurotransmitter receptors is the postsynaptic cell.

Below is an electron micrograph of a synapse, indicated by the blue arrow. Notice the cluster of synaptic vesicles near the synapse in the axon terminal. *Synaptic transmission was initially studied not between neurons but at the synaptic contact between the neuron and the muscle, which is called the neuromuscular junction. **Here are the steps of synaptic transmission.

First, the presynaptic axon terminal is depolarized by the action potential. Second, there are calcium channels in the axon terminal that are opened by depolarization.Third, calcium ions flow into the neuron through the open channels. A very strong concentration gradient is maintained in the cell (ECa is approximately +110 mV).Through a very complex series of protein interactions triggered by calcium, synaptic vesicles fuse with the presynaptic membrane. Fusion of the vesicles causes release of neurotransmitters stored in the vesicle. Neurotransmitter molecules are released into the synaptic cleft and bind with postsynaptic receptors. For the neuromuscular junction, the neurotransmitter is acetylcholine. Binding of acetycholine causes Na channels to open in the muscle, producing a depolarization of the muscle and leading to muscle contraction. *Botulinum prevents release at NMJ to give flaccid paralysisTetanus prevents inhibitory controlled of neural output, spastic paralysis, retrogradely transported and transcytosed*There are a variety of neurotransmitters released by neurons. Here is a partial list of the most important ones. As we just saw, acetylcholine is the neurotransmitter at the neuromuscular junction.

For inter-neuronal signaling, the main neurotransmitters are glutamate, GABA, and glycine. Glutamate is excitatory and depolarizes the cell, whereas GABA and glycine are inhibitory and often hyperpolarize the cell.

Other neurotransmitter modulate the actions of the main neurotransmitters or are most commonly released during specific behavioral states, such as sleep. These neurotransmitters are called neuromodulators and are extremely important. They are also the main type of receptors that are affected by recreational drugs. *Finally, we have reached across the synapse to the second cell. An excitatory neurotransmitter such as glutamate will produce a depolarization of the cell and make it more likely to fire an action potential. Conversely, an inhibitory neurotransmitter such as GABA will usually hyperpolarize the cell and decrease the probability that it will reach threshold*Green=fluorescein (fitc), red=rhodamine tritcBoth double labeledRed neurons are spiny stellate neurons that receive inputs from the short-latency visual thalamus, called the lateral geniculate.*