SYNAPTIC TRANSMISSION & TRANSMITTERS (Chapter 4)

Web Link: Neurotransmission.

http://www.csuchico.edu/psy/BioPsych/neurotransmission.html

How do neurons talk to each other?

             Sherrington, in 1906, suspected something special he called Synapse (Fig. 4.7)

                        Working on reflexes, he noted:

                                    reflexes are slower

                                    there is temporal and spatial summation

                                    there is excitation of some muscles and inhibition of others

The synapse: region where one axon terminal interacts with another neuron (Fig . 4.7).

Electrical synapses: gap junctions: Transmission from one neuron to the other is fast, and can be bidirectional. This type of synapsis is not plastic. Is found during some stages of development, and in some regions in adult specimens of some species. Most synapses in vertebrate brains are chemical. Recent studies show that gap junctions are found throughout the mammalian brain, associated with local neural inhibitory circuits.

Chemical synapses:

Transmission is mediated by chemical substances: neurotransmitters (Fig. 4.9; 4.10).

A neurotransmitter is a chemical substance that transmits the neural signal from one neuron to another.

Directed synapses: release of transmitters and postsynaptic receptors are close to each other (Fig. 4.7)

Nondirected synapses: release of neurotransmitters is at some distance from the receptors (Fig. 4.9)

 Otto Loewi demonstrated the chemical nature of synaptic transmission.

Otto Loewi’s dream experiment (1920). He was later awarded the Nobel Prize.

 Structure of the synapse (Fig. 4.7)

Presynapstic and postsynaptic membrane             

           Synaptic cleft: space between presynaptic and postsynaptic elements (0.05 mm)         

           Synaptic terminal contains synaptic vesicles which are full of neurotransmitters.

Sequence of events at a chemical synapse

-Neuron synthetizes neurotransmitters in cell body (e.g., peptide neurotransmitters). Small-molecule neurotransmitters can be synthetized at the axon terminal.

-Transmitters are transported to the axon terminals by microtubules. Transmitters are stored in synaptic vesicles.

-The arrival of an action potential at the synaptic button opens voltage-gated Ca++ channels.

-Ca++ ions flow into the synaptic button and vesicles attach to the presynaptic membrane.

-Synaptic vesicles docked to the presynaptic membrane empty the neurotransmitters into the synaptic cleft: this process is called exocytosis..

-The neurotransmitter binds to receptor molecules located in the postsynaptic membrane. A neurotransmitters is the ligand of its receptor.

-Neurotransmitter is either hydrolized by local enzymes, or re-uptaken and recycled. They can also diffuse away from the synapse.

-In some neurons, empty vesicles return to the cell body

Postsynaptic receptors activate postsynaptic ion channels (FIG. 4.11; 4.12).

            Characteristics of postsynaptic ion channels:

                        CHEMICALLY GATED (Lock-and-key mechanism).

                        NON-SPECIFIC

            Entrance of ions produce the Postsynaptic Potential

                        Postsynaptic potential changes can be excitatory or inhibitory. (Fig. 4.3)

1. Excitatory Postsynaptic Potentials (EPSP): transmitters open postsynaptic channels that allow Na+ to go in, and K+ to go out at the same time.

            EPSPs depolarize postsynaptic mebrane potential (less negative).

            EPSPs are smaller (about 60 mV) than Action Potentials (110 mV). Why?

2. Inhibitory Postsynaptic Potentials (IPSP): transmitter open postsynaptic channels to K+, or to Cl-.

            IPSP hyperpolarize post-synaptic mebrane potential (more negative).

Characteristics of postsynaptic potentials

            -Variable size: they can be of different size (graded, not all-or-nothing).

Size of Postsynaptic potentials depends on the amount of transmitter available in the cleft, and on the number of postsynaptic channels that open.

            -Variable duration.

                      Postsynaptic ions channels will remain open as long as transmitter interacts with the receptor.

Differences between Action Potentials and Postsynaptic Potentials:

Action Potential                        Post-Synaptic Potential

All-or-none, regenerative          Graded potential, variable in size and duration

Has threshold                           No threshold

Voltage gated channels             Chemically-gated channels

Specific ion channels                 Non-specific ion channels

Always depolatizing                  Can be depolarizing or hyperpolarizing

How does the Postsynaptic Potential affect the postsynaptic neuron? (Fig. 4.3)

            -Postsynaptic potentials are conducted passively to the axon hillock.

                        If EPSP depolarizes the potential at the axon hillock to threshold:

                                     action potentials are triggered at the hillock.

                        If IPSP hyperpolarizes the potential at the axon hillock:

                                     production of action potentials is inhibited at the hillock.

Information processing capabilities of synapses:

Spatial Summation (Fig. 4.4)

Temporal Summation (Fig. 4.5)

Action of neurotransmitter Receptors. When activated by transmitters, receptors can have three types of effects:

                        Ionotropic (Fig. 4.11). Activation of receptor leads to rapid opening of ion channels.

Glutamate opens channels that allow Na+ in and K+ out (excitatory)

GABA opens Cl- channels (inhibitory) (Fig. 4.18)

                        Metabotropic (Fig. 4.11). Activated receptors lead to chain of metabolic reactions (slow).

Activation of G-protein (coupled to guanosine triphosphate, GTP)

Increases concentration of second messenger (e.g., cyclic adenosine monophosphate, cyclic AMP), which can lead to:

                                                Opening or closing ion channels

                                                Alter the production of proteins

                                                Activate portion of chromosomes

                        Neuromodulator. Modulate the effect of neurotransmitters

Effects are more diffuse and slow. Resemble hormones

Usually act through second messenger systems

Presynaptic receptors

            Autoreceptors: Sensitive to the transmitter released by the same axon. Feedback (Fig. 4.16)

            Heteroreceptors: Responds to neurotransmitters from other neurons.

                        excitatory effect

                        inhibitory effect

NEUROTRANSMITTERS (see FIGURE)

When can a substance be called a neurotransmitter (criteria)? (Fig. 4.16)

            -Produced by cell

            -Present at the axon terminal

            -External application of substance mimics the natural effect of the substance

            -Existence of transmiter removal mechanism to stop the action. This can be :

Diffusion.

Enzymatic degradation (hydrolisis, transmitters are broken apart); e.g., Action of Acetylcholinesterase (AChase) on Acetylcholine (ACh).

Reuptake

There are many excitatory and inhibitory transmitters (Fig. 4.15).

By the size of the molecules, there are small and large-molecule transmitters.

The small-molecule transmitters include: aminoacids (aa, the building blocks of proteins), monoamines (synthetized from one aminoacid), the soluble gases, and acetylcholine.

The large-molecule transmitters are synthetized from many aminoacids. These include:

peptides, chains of aa that are fewer than 10 aa.

polypeptides are betwenn 10 - 100 aa.

proteins are more than 100 aa.

Small-molecule transmitters

1. Aminoacid neurotransmitters

Fast acting, and most common in the functioning of the nervous system.

excitatory: glutamate, aspartate, glycine, etc.

inhibitory: gamma-aminobutyric acid (GABA, derived from a simple modification of glutamate), etc

2. Monoamine neurotransmitters. Synthetized from only one aa (monoamino) 

            The effects are more diffuse.

            Most cells containing these transmitters are located in the brain stem .

                        a) Catecholamines, derived from the aa tyrosine-->

                                    L-DOPA--> Dopamine (dopaminergic neurons)

                                    dopamine-->Norepinephrine (noradrenergic neurons)

                                    norepinephrine-->epinephrine (adrenergic neurons). (Fig. 4.14)

                        b) Indolamines: synthetized from the aa tryptophan. Serotonin.

3. Soluble gases. These include nitric oxide and carbon monoxide. They are produced in the cytoplasm and quickly diffuse to other cells (they are soluble in the lipids of the membranes). They stimulate the production of second messengers, and are quickly deactivated.

4. Acetylcholine (Ach), excitatory, a small molecule synthetized from Choline by adding an acetyl group. Neurons that release acetylcholine are said to be cholinergic. ACh functions at many places:

In the autonomic nervous system, for example, Ach slows down the heart rate by acting on:

                        muscarinic ACh receptors. These receptors are blocked by atropine (belladonna)

In the somatic nervous system, Ach activates the synpase between nerves and skeletal muscle (neuromuscular junction) by acting on:

                        nicotinic ACh receptors. These receptors are blocked by curare.

Ach is deactivated by acetylcholinesterase (AChase), at the synaptic cleft.

Myasthenia gravis: autoimmune disease that causes reduction of Ach receptors, treated with AChase inhibitors such as Physiostigmine and Neostigmine, and by ACh agonists.

Large-molecule transmitters.

Peptides (neuropeptides). About 100 have been identified.

These transmitters tend to have widespread effect because they are often released into extracellular fluid, the ventricles or the blood stream.

Example : Oxytocin, corticotropin, growth hormone, vasopresin, insulin, endorphins, etc.

Some peptides are released into the blood stream by endocrine glands, but their role is not only in the endocrine system but also in the nervous system, where they can also be found.

How Drugs affect Synaptic Transmission. (Fig. 4.17)

Agonists: Drugs that facilitate or mimic the action of a neurotransmitter (Fig. 4.17).

For instance, Opium (effective in the treatment of pain, coughing, and diarrhea) contains morphine, agonist of endorphins, which are internal neuropeptides associated with analgesia and the experience of pleasure.

Benzodiazepines (marketed as Valium), have a sedative effect, they increase binding of GABA, increasing its inhibitory role.

Antagonists. Drugs that inhibit the action of a particular neurotransmitters (Fig. 4.17).

For instance, atropine is an antagonist to acetylcholine on the muscarinic Ach receptors. Atropine poisoning can be treated with physiostigmine, neostigmine.

d-Tubocurarine (curare) is an antagonist of ACh on the nicotinic (muscle) Ach receptors. Curare  produces paralysis (used by South american indians to paralyze their game and prevent  breathing). Curare poisoning can be treated with physiostigmine, neostigmine.

Botox (Botulinium toxin) is a neurotoxin released by a bacterium found in spoiled foods. It blocks the release of Ach. At small local doses, it can be used to reduce tremors and to reduce wrinkles.

(Section on Psychoactive drugs [page 95] will be covered in lecture on Drugs).