Chapter 5: Synaptic Transmission

Spatial Summation

*Spatial summation* is the adding together of EPSPs generated simultaneously at many different synapses on a dendrite

Temporal Summation

*Temporal summation* is the adding together of EPSPs generated at the same synapse if they occur is rapid succession, within about 1-15 msec of one another

Receptor Agonists

Drugs that bind to receptors, but instead of inhibiting them, they mimic the actions of the naturally occurring neurotransmitter. Example: nicotine

Length Constant (λ)

An index of how far depolarization can spread down a dendrite or axon, the longer the length constant, the more likely it is that EPSPs generated at distant synapses will depolarize the membrane at the axon hillock

Electrical Synapses

Are relatively simple in structure and function, and they allow the direct transfer of ionic current from one cell to the next. Electrical synapses occur at specialized sites called gap junctions

Effects of Transmitter-Gated Ion Channels Being Permeable to Na^+

As as a rule, if the open channels are *permeable to Na^+*, the net effect will be to depolarize the postsynaptic cell from the resting membrane potential. Because it tends to bring the membrane potential toward threshold for generating action potentials, this effect is said to be *excitatory*

Decrease in Depolarization with Distance

As the synaptic current proceeds down the dendrite and farther from the synapse after synaptic transmission, the EPSP amplitude will diminish because of the leakage of ionic current through membrane channels

Spontaneous Release of Neurotransmitter

At many synapses, exocytosis of vesicles occurs at some very low rate in the absence of presynaptic simulation. The size of the postsynaptic response to this spontaneously released neurotransmitter can be measured electrophysiologically

Desensitization

At the neuromuscular junction, uninterrupted exposure to high concentrations of ACh after several seconds leads to a process called *desensitization*, in which, despite the continued presence of ACh, the transmitter-gated channels close. This desensitized state can persist for many seconds even after the neurotransmitter is removed.

Regulatory Effect of Autoreceptors

Autoreceptors inhibitory effects allow a presynaptic terminal to regulate itself. Autoreceptors appear to function as a sort of safety valve to reduce release when the concentration of neurotransmitter around the presynaptic terminal gets too high

Metabotropic Receptors

Because G-protein-coupled receptors can trigger widespread metabolic effects, they are often referred to as *metabotropic receptors*

Bidirectionality Affect on Postsynaptic Potential

Because most electrical synapses are bidirectional, when that 2nd neuron generates an action potential, it will in turn induce a PSP in the 1st neuron

Two General Categories of CNS Synapses

CNS synapses may be further classified into two general categories based on the appearance of their presynaptic and postsynaptic membrane differentiations. The categories are... 1. Gray's type I synapses.. 2. Gray's type II synapses

Neuromuscular Junction

Chemical synapses also occur between the axons of motor neurons of the spinal cord and skeletal muscle. Such a synapses is called a *neuromuscular junction*, and it has many of the structure features of chemical synapses in the CNS

Electrical Synapses Role in Brain

Current that flows through gap junctions during membrane oscillations and action potentials serves to coordinate and synchronize the activity of inferior olivary neurons, and this in turn may help to control the fine timing of motor control

Membrane Differentiations

Dense accumulations of protein adjacent to and within the membranes on either side of the synaptic cleft are collectively called *membrane differentiations*

Types of Synaptic Transmission

Different neurons in the brain release different neurotransmitters. The speed of synaptic transmission varies widely.

Effector Proteins

Effector proteins can be G-protein-gated ion channels in the membrane, or they can be enzymes that synthesize molecules called *second messengers* that diffuse away in the cytosol

Electrically Coupled Cells

Electrical current(in the form of ions) can pass through these channels, cells connected by gap junctions are said to be *electrically coupled*

Fast Synaptic Transmission

Fast forms of synaptic transmission last from about 10-100 msec, and most CNS synapses are mediated by the amino acids *glutamate(Glu), gamma-aminobutyric acid(GABA), or glycine(Gly)*. The amine *acetylcholine(ACh)* mediates fast synaptic transmission at all neuromuscular junctions

Neurotransmitter Release

Is triggered by the arrival of an action potential in the axon terminal. The depolarization of the terminal membrane causes *voltage-gated calcium channels* in the active zones to open

Bidirectionality of Gap Junction Channels

Most gap junctions allow ionic current to pass equally well in both directions; therefore, unlike the vast majority of chemical synapses, *electrical synapses are bidirectional*

Chemical Synapses

Most synaptic transmission in the mature human nervous system is chemical. The presynaptic and postsynaptic membranes at chemical synapses are separated by a synaptic cleft that is 20-50 nm wide, 10 times the width of separation at gap junctions

Neuromuscular Synaptic Transmission

Neuromuscular synaptic transmission is fast and reliable. An action potential in the motor axon always causes an action potential in the muscle cell it inervates. This reliability is accounted for by its size(largest synapses in the body) and its large number of active zones

Enzymatic Destruction of Neurotransmitters in Synaptic Cleft

Neurotransmitter action can also be terminated by enzymatic destruction in the synaptic cleft itself. This is how ACh is removed at the neuromuscular junctio. The enzyme acetylcholinesterase(AChE) is deposited in the cleft by the muscle cells. AChE cleaves the ACh molecule, rending it inactive at the ACh receptors

1st Step of Transmitter Action for G-Protein-Coupled Receptors

Neurotransmitter molecules bind to the receptor proteins embedded in the postynaptic membrane

Nerve Gases Used as Chemical Weapons

If the AChE is inhibited, as it is by various nerve gases used as chemical weapons, the ACh receptors will become desensitized and the neuromuscular transmission will fail

Axodendritic Synapse

If the postsynaptic membrane is on a dendrite, the synapses is said to be *axodendritic*

Axosomatic Synapse

If the postsynaptic membrane is on the cell body, the synapse is said to be *axosomatic*

Effects of Transmitter-Gated Ion Channels Being Permeable to Cl^-

If the transmitter-gated channels are *permeable to Cl^-*, the usual net effect will be to hyperpolarize the postsynaptic cell from the resting membrane potential(because the chloride equilibrium potential is usually negative). Because it tends to bring the membrane potential away from threshold for generating action potentials, this effect is said to be *inhibitory*

CNS Chemical Synapses

In the CNS, different types of synapses may be distinguished by which part of the neuron is postsynaptic to the axon terminal

Inducing Opening of Transmitter-Gated Ion Channels

In the absence of neurotransmitter, the pore is usually closed. When neurotransmitter binds to a specific sites on the extracellular region of the channel, it induces a conformation change and causes the pore to open. The functional consequence of this depends on which ions can pass through the pore

Receptor Antagonists

Inhibitors of neurotransmitter receptors, called *receptor antagonists*, bind to the receptors and block (antagonize) the normal action of the transmitter. Example: curare - paralyzing poison

Glia Cells Role in Recycling Neurotransmitters from Synaptic Cleft

Neurotransmitter transporters also exist int he membranes of glia surrounding the synapse, which assist in the removal of neurotransmitters from the cleft

Neurotransmitter Receptors and Effectors

Neurotransmitters released into the synaptic cleft affect the postsynaptic neuron by binding to specific receptor proteins that are embedded in the postsynaptic density. Neurotransmitter receptors can be classified into two types: *transmitter-gated ion channels* and *G-protein-coupled receptors*

Nicotinic ACh Receptors

Nicotine binds to and activates the ACh receptors in skeletal muscle. In fact, the ACh-gated ion channels in muscle are also called *nicotinic ACh receptors*, to distinguish them from other types of ACh receptors

Presynaptic Side of Membrane Differentiations

On the presynaptic side, proteins jutting into the cytoplasm of the terminal along the intracellular face of the membrane sometimes look like a field of tiny pyramids

Recycling Neurotransmitters from Synaptic Cleft

Once inside the cytosol of the terminal from reuptake, the transmitters may be reloaded into synaptic vesicles or enzymatically degraded and their breakdown products recycled

EPSPs are Quantized

Postsynaptic EPSPs at a given synapse are *quantized*; they are multiples of an indivisible unit, the *quantum*, which reflects the number of transmitter molecules in a single synaptic vesicle and the number of postsynaptic receptors available at the synapse

Autoreceptors

Presynaptic receptors that are sensitive to the neurotransmitter released by the presynaptic terminal.

Transporters

Special proteins embedded in the vesicle membrane that concentrate amino acid and amine neurotransmitters inside the vesicle.

Gray's Type I Synapses

Synapses in which the membrane differentiation on the postsynaptic side is thicker than that on the presynaptic side are called *asymmetrical synapses, or Gray's type I synapses*. These are usually excitatory synapses

Gray's Type II Synapses

Synapses in which the membrane differentiations are of similar thickness are called *symmetrical synapses, or Gray's type II synapses*. These are usually inhibitory synapses

Optimized Synaptic Current Flow

Synaptic current will flow farther down a wide dendrite(low internal resistance(ri)) with few open membrane channels(high membrane resistance(rm))

3rd Step of Transmitter Action for G-Protein-Coupled Receptors

The activated G-proteins activate "effector" proteins

Amplitude of Postsynaptic EPSP

The amplitude of the postsynaptic EPSP evoked by a presynaptic action potential is simply an integer multiple(1x, 2x, 3x, etc.) of the mini amplitude(mini amplitude is generated by transmitter contents of one vesicle)

What Constitutes Membrane Resistance

The membrane resistance depends on the number of open ion channels, which changes from moment to moment depending on what other synapses are active

Most Elementary Postynaptic Response

The most elementary postynaptic response is the opening of a single transmitter-gated channel. Inward current through these channels depolarizes the postsnaptic membrane, causing the EPSP

Motor End-Plate

The postsynaptic membrane, also called the *motor end-plate*, contains a series of shallow folds The presynaptic active zones are precisely aligned with these junctional folds, and the postsynaptic membrane of the folds is packed with neurotransmitter receptors. This ensures that many neurotransmitter molecules are focally released onto a large surface of chemically sensitive membrane

Presynaptic Side of Synapse

The presynaptic side of the synapse, also called the presynaptic element, is usually an axon terminal. The terminal typically contains dozens of small membrane-enclosed spheres, each about 50 nm in diameter, called synaptic vesicles

Synaptic Integration

The process by which multiple synaptic potentials combine within one postsynaptic neuron

Synaptic Trasmission

The process of information transfer at a synapse

Postsynaptic Density

The protein thickly accumulated in and just under the postsynaptic membrane. The postsynaptic density contains the neurotransmitter receptors, which convert the intercellular chemical signal(neurotransmitter) into an intracellular signal(a change in the membrane potential or a chemical change) in the postsynaptic cell

Active Zones

The pyramids, and the membrane associated with them, are the sites of neurotransmitter release, called *active zones*. Synaptic vesicles are clustered in the cytoplasm adjacent to the active zones

Selectivity of Transmitter-Gated Ion Channels

These channels generally do not show the same degree of ion selectivity as do voltage-gated channels. The ACh-gated ion channels at the neuromuscular junction are permeable to both Na^+ and K^+.

Voltage-Gated Calcium Channels

These membrane channels are similar to Na^+ channels, except are permeable to Ca^2+ instead of Na^+. The internal calcium ion concentration at rest is very low, therefore, Ca^2+ will flood the cytoplasm of the axon terminal as long as the calcium channels are open. The resulting elevation in [Ca^2+]i is the signal that causes neurotransmitter to be released from synaptic vesicles

Synaptic Vesicles

These vesicles store neurotrasmitter, the chemical used to communicate with the postsynaptic neuron

Gap Junction Channel

This channel allows ions to pass directly from the cytoplasm of one cell to the cytoplasm of the other. The pore of most gap junction channels is relatively large(1-2 nm), making it big enough for all the major cellular ions and many small organic molecules to pass through

Synaptic Cleft

This cleft is filled with a matrix of fibrous extracellular protein. One function of this matrix is to serve as a "glue" that binds the pre- and postsynaptic membranes together.

Electrical Synaptic Transmissions

Transmission at electrical synapses is very fast and, if the synapse is large, nearly fail-safe. This allows for an action potential in the presynaptic neuron to be produced, with very little delay, in the postsynaptic neuron

Function of Autoreceptors

Typically, autoreceptors are G-protein-coupled receptors that stimulate second messenger formation. The consequences of activating these receptors vary but a common effect is inhibition of neurotransmitter release and , in some cases, inhibition of neurotransmitter synthesis

Speed of Exocytosis of Secretory Granules

Unlike the fast release of amino acid and amine neurotransmitters, the release of peptides is a leisurely process, taking 50 msec or more

Secretory Granules

Vesicles with the axon terminal that are larger than synaptic vesicles, each about 100 nm in diameter. Secretory granules contain soluble proteins that appears dark in the electron microscope, so they are sometimes called large, *dense-core vesicles*

Various Shapes and Sizes of CNS Synapses

When a presynaptic axon contacts a postsynaptic dendritic spine, it is called *axospinous*. In certain specialized neurons, dendrites actually form syanapses with one another; these are called *dendrodentritic synapses*. The sizes and shapes of CNS synapses also vary widely

Inhibitory Synapses

When the action of a synapse is to take the membrane potential away from the action potential threshold. Inhibitory synapses exert a powerful control over a neurons output

Axoaxonic Synapse

When the postsynaptic membrane is on another axon, the synapse is said to be *axoaxonic*

Postsynaptic Potential(PSP)

When two neurons are electrically coupled(connected by gap junction channel) , an action potential in the presynaptic neuron causes a small amount of ionic current to flow across the gap junction channels into the other neuron. This current causes an electrically mediated *postsynaptic potential (PSP)* in the 2nd neuron

Clearing Neurotransmitter from Synaptic Cleft After Use

Once the released neurotransmitter has interacted with postsynaptic receptors, it must be cleared from the synaptic cleft to allow another round of synaptic transmission

Inhibitor Drugs

A class of drug action, which is to inhibit the normal function of specific proteins involves in synaptic transmission.

Quantal Anaylsis

A method of comparing the amplitudes of miniature and evoked PSPs. Can be used to determine how many vesicles release neurotransmitter during normal synaptic transmission

Synapse

A specialized site of contact at which the transfer of information from one neuron to another occurs

Inhibitory Postsynaptic Potential (IPSP)

A transient hyperpolarization of the postynaptic membrane potential caused by the presynaptic release of neurotransmitter. Synaptic activation of glycine-gated or GABA-gated ion channels cause an IPSP. Inhibitory synapses are permeable to only Cl^-

Excitatory Postsynaptic Potential (EPSP)

A transient postsynaptic membrane depolarization caused by the presynaptic release of neurotransmitter. Synaptic activation of ACh-gated and glutamate-gated ion channels causes EPSPs

Recovery of Neurotransmitters from Synaptic Cleft

For most of amino acid and amine neurotransmitters, diffusion is aided by their reuptake into the presynaptic axon terminal. Reuptake occurs by the action of specific neurotransmitter transporter proteins located in the presynaptic membrane

Gap Junctions

Gap junctions occur between cells in nearly every part of the body and interconnect many non-neural cells, including epithelial cells, smooth and cardiac muscle cells, liver cells, some glandular cells, and glia. When gap junctions interconnect neurons, they can function as electrical synapses. At a gap junction, the membranes of two cells are separated by only about 3 nm, and this narrow gap is spanned by clusters of special proteins called connexins

Transmitter-Gated Ion Channels

Receptors known as *transmitter-gated ion channels* are membrane-spanning proteins consisting of four or five subunits that come together to form a pore between them.

Exocytosis of Secretory Granules

Release peptide neurotransmitters by exocytosis, in a calcium-dependent fashion, but typically not at the active zones. Peptide neurotransmitters are usually not released in response to every action potential invading the terminal. Instead, the release of pepetides generally requires high-frequency trains of action potentials, so that the [Ca^2+]i throughout the terminal can build to the level required to trigger release away from the active zones.

EPSP Summation

Represents the simplest form of synaptic integration in the CNS. There are two types of summation: spatial and temportal

Second Messengers

Second messengers can activate additional enzymes in the cytosol that can regulate ion channel function and alter cellular metabolism

Different Types of Neurotransmitters in the Same Axon Terminal

Secretory and synaptic vesicles are frequently observed in the same axon terminals, and so, peptides often exist in the same axon terminal that contain amine or amino acid neurotransmitters, but these different neurotransmitters are released under different conditions

Slow Synaptic Transmission

Slower forms of synaptic tranmission may last from hundreds of milliseconds to minutes; they can occur in the CNS and in the periphery and are mediated by transmitters from all three chemical categories

Principles of Chemical Synaptic Transmission

The basic requirements of chemical synaptic transmission... 1. Mechanism for synthesizing neurotransmitter and packing it into synaptic vesicles.. 2. Mechanism for causing vesicles to spill their contents into the synaptic cleft in response to a presynaptic action potential.. 3. Mechanism for producing an electrical or biochemical response to neurotransmitter in the postsynaptic neuron.. 4. Mechanism for removing neurotransmitter from the synaptic cleft.. 5. All these things have to occur very rapidly, within milliseconds

Factors Affecting the Effectivenss of Excitatory Synapses

The effectiveness of an excitatory synapse in triggering an action potential depends on how far the synapse is from the spike-initiation zone and on the properties of the dendritic membrane

What Constitutes Internal Resistance

The internal resistance depends only on the diameter of the dendrite and the electrical properties of the cytoplasm; consequently, it is relatively constant in a mature neuron

Three Chemical Categories of Neurotransmitters

The major neurotransmitters fall into 1 of 3 chemical categories... 1. Amino acids.. 2. Amines.. 3. Peptides... The *amino acid and amine neurotransmitters* are all small organic molecules containing at least one nitrogen atom, and they are stored in and released from synaptic vesicles. *Peptide neurotransmitters* are large molecules - chains of amino acids - stored in and released from secretory granules

2nd Step of Transmitter Action for G-Protein-Coupled Receptors

The receptor proteins activate small proteins, called *G-proteins*, which are free to move along the intracellular face of the postynaptic membrane

Membrane Resistance (rm)

The resistance to current flowing across the membrane. Most current will take the path of least resistance; therefore, the value of length constant will increase as membrane resistance increases because more depolarizing current will flow down the inside of the dendrite rather than "leaking" out the membrane

Internal Resistance(ri)

The resistance to current flowing longitudinally down the dendrite. The value of the length constant (λ) will decrease as internal resistance increases because more current will then flow across the membrane

Neuropharmacology

The study of the effects of drugs on nervous system tissue

Miniature Postsynaptic Potential(Mini)

The tiny response of postynaptic membrane to spontaneous release of neurotransmitter is a *miniature postsynaptic potential*, often called simply a mini. Each mini is generated by the transmitter contents of one vesicle

Neural Computation

The transformation of many synaptic inputs into a single neuronal output

2 Factors Affecting Length Constant

The value of the length constant (λ) depends on two factors... 1. The internal resistance (ri).. 2. The membrane resistance (rm)

Endocytosis

The vesicle membrane that became part of the presynaptic membrane is later recovered by the process of *endocytosis*, and the recycled vesicle is refilled with neurotransmitter

Exocytosis

The vesicles release their contents by this process, in which the membrane of the synaptic vesicle fuses to and becomes incorporated into the presynaptic membrane at the active zone, allowing the contents of the vesicle to spill out into the synaptic cleft

G-Protein-Coupled Receptors

There are 3 types of neurotransmitters acting on *G-protein-coupled receptors* and all can have slower, longer lasting, and must more diverse postynaptic actions than fast chemical synaptic transmission. This type of transmitter action involves 3 steps

Connexins

There are about 20 different subtypes of connexins, about half of which occur in the brain. 6 connexin subunits combine to form a gap junction channel