Dr. Chris Doumen Week 6

2401 : Anatomy/Physiology Transmiss ion at Synapses Communication between neurons is at the basis of the overall function of the nervous system. It depends on the flow of information through elaborate circuits of neurons and the integration of the incoming impulses. Synapses are the site of communication between 2 or more neurons. It mediates the transfer of information and it is the place where the signal are transmitted, blocked or modulated. Each neuron in the brain is believed to form about 1000 synaptic endings. With around 1012 neurons in the brain, this yields a staggering 1015 number of synapses and possible pathways for impulses to travel.

Terminology: • The neuron that sends the signal =

pre-synaptic neuron • The neuron receiving the signal =

post-synaptic neuron • If the signal travels from axon to

dendrite = axodendritic synapse • If the signal goes from axon to cell

body = axosomatic synapse • If signal travels from axon to axon =

axoaxonic synapse .

NeuroPhysiology

Collin County Community

College District

TextBook Readings ♦ Pages 408 through 420 ♦ Make use of the figures

in your textbook ; a picture is worth a thousand words !

♦ Work the Problems and

Questions at the end of the Chapter

There are two types of Synaptic transmission 1. Electrical Synapses

• arriving impulse forces ions to flow through gap junctions that connect to adjacent cells

• electrical disturbance depolarizes the postsynaptic cell • they result in fast transmission and capable to synchronize the activity of

interconnecting cells

2. Chemical Synapses • The synapse is characterized by a synaptic cleft which separates the two

neurons ( ~ 20-50 nm) ….. So there is no physical connections • Impulses cannot jump this cleft . That's why the organization across a

synapse is such that the presymaptic neuron terminal contains vesicles with neurotransmitters ( the chemical signal) and the postsynaptic neuron membrane contains the receptor proteins for this messenger

• The presynaptic impulse which is ionic is converted to a chemical signal (neurotransmitters) that crosses the cleft and influence the ion channels in the postsynaptic neuron, and consequently the membrane potential in that area.

Post Synaptic Potentials The neurotransmitters bind to specific receptors, located in the postsynaptic membrane. These receptors are chemically gated ion channels and hence, if opened by binding the neurotransmitter, will result in a specific ion flow. Thus, we will be creating some form of a graded potential ( can you explain why ?)

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This raises intracellular Ca 2+ levels which promotes the fusion of the intracellular vesicles with the plasma membrane. Exocytosis follows, releasing the stored neurotransmitters from the vesicles into the synaptic cleft. The amount of neurotransmitter released is proportional to the Calcium influx. The neurotransmitters diffuse across the cleft and bind to receptors ( specified membrane proteins) on the post synaptic membrane The transmitter- receptor complex promotes the opening of specific postsynaptic ion channels. In contrast to the other voltage-gated ion channels, these are chemically-gated ion channels.

Sequence of Events at Chemical Synapses

The depolarization of the terminal bulbs at the axons of presynaptic neurons, opens voltage gated Ca2+ channels located in the plasma membrane of the terminal bulb. Since Ca 2+ is high on the outside and low in the axoplasm, calcium will flow inwards

Since the postsynaptic cell does not contain vesicles with neurotransmitters, and the presynaptic membrane does not contain receptors for neurotransmitters, it follows that the transmission of the signal can only proceed in one direction.

• If the neurotransmitter causes a depolarization of the postsynaptic membrane, it is called an Excitatory Postsynaptic Potential (EPSP). They usually are the result of the opening of chemically gated Na+ channels in a small area. It can also be produced by the closing of K+ channels. If several of these EPSP's sum up to bring the depolarization above threshold in the axon hillock area, voltage gated Na+ channels will open and result in an AP.

• If the neurotransmitter results in a hyperpolarization, it will drive the MP to a greater negative potential and bring it further away from the threshold level. This is an Inhibitory Postsynaptic Potential. They are the result of opening of chemically gated K+ or Cl- ion channels (but can be due to the closing of Na+ channels as well)

Removal of Neurotransmitter Removal of the released neurotransmitter(s) is essential for normal synaptic function. It prevents that the stimulus would last indefinitely and also allows new incoming signals to have their effect on the postsynaptic receptors. The effect of the neurotransmitter last only a few milliseconds as they are removed and the signal thus terminated by 3 mechanisms

• Diffusion of the neurotransmitters away from the synaptic cleft • Degradation of the neurotransmitter by enzymes associated in the postsynaptic

membrane or present in the synapse. • Removal of the transmitter by reuptake into the presynaptic terminal of neighboring

cells that contain specific neurotransmitter transporters A clinical aspect of this is that Cocaine blocks the reuptake of Dopamine, a neurotransmitter found in the brain, and thus results in excessive stimulation (euphoria).

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Spatial and Temporal Summation of PSP's A single EPSP cannot induce an action potential in the postsynaptic neuron. They last a few milliseconds and fade away over short distances. However if a postsynaptic receives thousands of presynaptic inputs at the same time or if few presynaptic neurons fire in rapid sequence on a single postsynaptic membrane, the probability to reach threshold increases greatly. The integration of all the inputs is called summation. The greater the summation, the greater the chance that a nerve impulse will be generated in the postsynaptic neuron. Two types of summation occur : Temporal summation : (example A below)

• buildup of NT released by a single presynaptic endbulb but firing 2 or more times in rapid sequence

• before an EPSP dies out another one is generated and the result is a EPSP of slightly higher magnitude. Many such sequences result in greater EPSP's

Spatial summation : (example A+B, or C+A) • summation as a result of build-up of NT released by many

presynaptic neuron terminals • the many EPSP's or ISPN’s produced sum up

The postsynaptic neuron receives not only EPSP's but also many IPSPs. All of these signals are summed up and the neuron keeps a running tab of all this. The sum of all these effects, excitatory and inhibitory, determines the effect on the postsynaptic neuron. Some of the Differences between AP and PSP's should be evident by now

• Propagation : AP's do propagate by a positive feedback -- PSP's don't ; they fade away over distance since they are graded potentials

• Amplitude: AP's are all or none (same amplitude) -- PSP's are graded, they depend on the strength of stimulation ; they depend on summation

• Refractory period: AP's have one -- PSP's don't

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Modulation of the s ignal at the synapse These mechanisms modify the quantity of the Neurotransmitter released

Facilitation :

• occurs when a presynaptic axon bulb is stimulated to release more NT • mediated by the end-bulb of an axon of another neuron that synapses with the

excitatory ending; it is thus an axoaxonic synapse stimulation • the impulse from the facilitating neuron causes either

• a prolonged depolarization or a direct opening of Ca-channels • both events will result in more Calcium influx and thus additional NT release

Inhibition :

• similar as above, but in this case the effect of the other neuron is inhibitory • the stimulus by the second axo-neuron on the first one results thus in

• a shortened depolarization ( opening of K+ or Cl- channels) or • the closure of calcium channels

• the result in this event is a reduced calcium flux and thus less NT release

Facilitation also refers to any stimuklus that brings the resting membrane potential closer to threshold, and thus closer to an action potential.

Caffeine for example lowers the threshold level of a neuron while Nicotine stimulates Acetylcholine receptors, bringing about EPSP’s.

Neurotransmitters and Their receptors Neurotransmitters are, along with the electrical signals, the languages of the nervous system. At present over 50 different chemicals are know as NT or are NT candidates. The important criteria for a chemical to be recognized as a NT are: • It must be present in the presynaptic terminal and be discharged when the neuron is

stimulated • When applied externally to the postsynaptic neuron membrane, it must produce ion fluxes

(PSP's) • There must be some natural means of removing the NT from the synaptic junction Although most neurons release only one NT, some can release several different ones, apparently dependent of the type of signal frequency it receives.

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Chemical Classification AcetylCholine (ACh) • Is the best studied Neurotransmitter (NT).

It is released by all neurons that stimulate skeletal muscle (motor neurons of PNS) and some neurons in CNS.

• Thus ACh is an excitatory NT at the neuromuscular junction (produces EPSP’s) but can be inhibitory such as in the vagus nerve to the heart (autonomic nervous system)

• In the neuromuscular junction, the enzyme Acetylcholinesterase (AChE) degrades ACh to Acetic acid and Choline. AchE is located on the postsynaptic membrane.

• Choline is recaptured by the presynaptic bulbs and used to make new ACh • There are two types of receptors for ACh

• Nicotinic Receptors : they contain ion channels and result in EPSP's • Muscarinic Receptors : work via G-proteins, a membrane system of proteins that

activates enzymes and ion channels. The result can be EPSP or IPSP ! Biogenic Amines • These are neurotransmitters that derived from amino acids • Include the catecholamines dopamine, norepinephrine, epinephrine and the indolamines

(histamine, serotonin) • The above mentioned catecholamines are synthesized from the amino acid (a.a.) Tyrosine

in a sequential fashion. But the neuron contains only those enzymes needed for the production of the NT it releases.

• Serotonin is made from the a.a. tryptophane, while histiamine is made from the a.a. histidine

• Biogenic amines are broadly used in the brain. Imbalances in the NT are associated with mental illness. ( too much dopamine with schizophrenia; loss of serotonin receptors is seen in Alzheimer patients)

• Catecholamines also play a role in motor neurons of autonomic nervous system • Some drugs bind to biogenic amine receptors and cause hallucinations ( LSD, mescaline) Amino Acids • So far they have only been found to be active in the CNS • Glutamate, Aspartate have powerful excitatory effects in the brain • Gamma Amino Butyric Acid (GABA) and glycine results in IPSP's (open Cl- channels).

GABA is mostly found in the brain, while glycine predominates in the spinal cord

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Peptides • Neuropeptides include a broad spectrum of molecules with diverse effects • Substance P is a mediator of pain signals • Endorphins and enkaphalins act as natural opiates ( reduce perception of pain) Dissolved Gases • These are very unusual messengers since they are small gases that are not stored in

vesicles but produced on demand. • Nitric Oxide (NO), produced by the enzyme Nitric Oxide Syntahse

• NO Binds to intracellular guanylyl cyclase , which makes cyclic GMP • cGMP can activate many cellular processes • NO is very short lived

• Carbon monoxide (CO) behaves similar and stimulates synthesis of cGMP as well. Neurotransmitters and Pharmacology The fact that synaptic transmission is mostly chemical is of great pharmaceutical importance. Allows pharmacologist to design drugs that can interact at that level. This chemical transmission can thus be modified in several ways

• Stimulate or inhibit NT synthesis • Block or enhance NT release • Stimulate or inhibit NT removal • Block or activate the receptor site

Examples of NT action and modulation • The Botulinum toxin ( from Clostridium botulinum) grows in improperly canned food. The toxin

inhibits the release of ACh and thus weakens muscle contraction. It is very toxic at small doses. Yet, it is used clinically to treat people with strabismus (crossed eyes) and blepharospam ( uncontrollable winking)

• Curare is a derivative of a South American plant which blocks ACh receptors in the NMJ. It

causes muscular paralysis and it is used by the native indians to shoot down birds and monkeys with poisonous arrows. However it found its way in medical practice as well.

• Nerve gas Diisopropyl Fluorphosphate (DPFP) and Sarin are anticholinesterase agents. This

usually has its effect on the diaphragm and causes prolonged contraction ( with no exhalation possible)

• Prozac blocks re-uptake of serotonin into the presynaptic neuron. LSD blocks serotonin

receptors.

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• NMDA-receptors are receptors that bind glutamate and cause changes in ion fluxes

( it is an ionotropic receptor). Angel dust apparently works by altering the acitivity of this NMDA receptor.

Examples of NeuroToxins and Neuronal Diseases Myasthenia gravis is an autoimmune disease where one's own antibodies block ACh receptors at the neuromuscular junction. This weakens muscle contraction and often results in paralysis. Both Neostigmine and Physostigmine are used to counteract this disease. The chemicals are fungi products that inactivate the enzyme that breaks down ACh ( thus anticholinestarase agents). Multiple Sclerosis is apparently a disorder of the immune system , resulting in de-myelination of neurons in the brain, spinal cord and peripheral nervous sysyetm Tay Sach disease is a genetic disorder, mostly found in the Jewish population. It results in build-up of a membrane protein (gangliosides) in the lysosomes of the neurons. The results are fatal and the affected child does dies at an early age. Tetrodotoxin (TTX) is a chemical found in pufferfish and some other animals. It is a potent voltage gated Na+ channel blocker. The results of an excessive dose of this drug should be obvious when thinking about the role of that channel in action potentials. It has been suggested that voodoo rituals use animals tissues that contain high levels of this chemical ( causes paralysis of skeletal muscles and can thus be fatal ). Heavy metals tend to cause de-myelination and damage the glial cells. Lidocaine ( and similar drugs) is an effective local anesthetics since they are reversible voltage gated Na-channel blockers. Your dentist uses it quite often to numb your teeth.

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