Chapter 6: Synapses and Neurotransmitters

excitatory synapse

The membrane potential of a postsynaptic neuron is brought closer to threshold (depolarized) at an excitatory synapse

inhibitory synapse

membrane potential is either driven farther from threshold (hyperpolarized) or stabilized at its resting potential at an inhibitory synapse

convergence

Hundreds or thousands of synapses from many different presynaptic cells can affect a single postsynaptic cell

-> Convergence allows information from many sources to influence a cell's activity

divergence

a single presynaptic cell can send branches to affect many other postsynaptic cells

-> divergence allows one cell to affect multiple pathways.

electrical synapses

the plasma membranes of the presynaptic and postsynaptic cells are joined by gap junctions (Figure 6.26a; refer also to Figure 3.9).

These allow the local currents resulting from arriving action potentials to flow directly across the junction through the connecting channels from one neuron to the other.

chemical synapse

The axon of the presynaptic neuron ends in slight swellings, the axon terminals, which hold the synaptic vesicles that contain neurotransmitter molecules.

synaptic vesicles

Tiny pouches or sacs in the axon terminals that contain chemicals called neurotransmitters.

postsynaptic density

The postsynaptic membrane adjacent to an axon terminal has a high density of membrane proteins that make up a specialized area called the postsynaptic density

synaptic cleft

A 10 to 20 nm extracellular space, the synaptic cleft, separates the presynaptic and postsynaptic neurons and prevents direct propagation of the current from the presynaptic neuron to the postsynaptic cell.

Instead, signals are transmitted across the synaptic cleft by means of a chemical messenger—a neurotransmitter—released from the presynaptic axon terminal.

Study and Review 6.8

Excitatory synapse: brings the membrane of a postsynaptic cell closer to threshold

Inhibitory synapse: prevents a postsynaptic cell from approaching threshold by hyperpolarizing or stabilizing the membrane potential

Whether a postsynaptic cell fires an action potential depends on the number of synapses that are active and whether they are excitatory or inhibitory.

Electrical synapses: consist of gap junctions that allow current to flow between adjacent cells

Chemical synapses: Neurotransmitters stored in synaptic vesicles are released by a presynaptic axon terminal into the synaptic cleft, where they transmit the signal from a presynaptic neuron to an adjacent postsynaptic neuron at a region called a postsynaptic density.

active zones

Prior to activation, many vesicles are docked on the presynaptic membrane at release regions known as active zones, whereas others are dispersed within the terminal

SNARE proteins

Prior to the arrival of an action potential, vesicles are loosely docked in the active zones by the interaction of a group of proteins, some of which are anchored in the vesicle membrane and others that are found in the membrane of the terminal. These are collectively known as SNARE proteins (soluble N-ethylmaleimide-sensitive factor attachment protein receptors).

synaptotagmins

Calcium ions entering during depolarization bind to a separate family of proteins associated with the vesicle, synaptotagmins, triggering a conformational change in the SNARE complex that leads to membrane fusion and neurotransmitter release.

After fusion, vesicles can undergo at least two possible fates

Study and Review 6.9

Depolarization of an axon terminal opens voltage-gated Ca2+ channels in the membrane.

-> Ca2+ diffuses through channels down its electrochemical gradient into the cytosol of the terminal.

-> Increased Ca2+ concentration causes cytosolic proteins synaptotagmins and SNAREs to induce vesicles (docked at active zones of a presynaptic neuron) containing neurotransmitter to fuse with the plasma membrane, thereby releasing neurotransmitter into the synaptic cleft.

ionotropic receptors

Neurotransmitters rapidly and reversibly bind to receptors on the plasma membrane of the postsynaptic cell. The activated receptors themselves may be ion channels, which designates them as ionotropic receptors

metabotropic receptors

Alternatively, the receptors may indirectly influence ion channels through a G protein and/or a second messenger, a type referred to as metabotropic receptors

reuptake

Unbound neurotransmitters are removed from the synaptic cleft when they:

are actively transported back into the presynaptic axon terminal for reuse (in a process called reuptake)

excitatory postsynaptic potential (EPSP)

a slight depolarization of a postsynaptic cell, bringing the membrane potential of that cell closer to the threshold for an action potential

--> The EPSP is a depolarizing graded potential that decreases in magnitude as it spreads away from the synapse by local current. Its only function is to bring the membrane potential of the postsynaptic neuron closer to threshold.

inhibitory postsynaptic potential (IPSP)

At inhibitory chemical synapses, the potential change in the postsynaptic neuron is generally a hyperpolarizing graded potential called an inhibitory postsynaptic potential (IPSP)

Study and Review 6.10

Postsynaptic cell neurotransmitter receptors may be ionotropic, which contain an ion channel in their structure, or metabotropic, which are linked with second-messenger systems and indirectly alter ion channels.

Excess neurotransmitters are removed from the synaptic cleft by:

-> reuptake into the presynaptic cell for re-use

-> enzymatic degradation into inactive fragments

-> transport into glial cells

Excitatory postsynaptic potential (EPSP): the electrical response (depolarization) in a postsynaptic cell at an excitatory chemical synapse

-> usually due to Na+ flux through nonspecific cation channels opening in postsynaptic cell

Inhibitory postsynaptic potential (IPSP): either a hyperpolarization or a stabilization of the membrane potential at an inhibitory chemical synapse

-> usually due to opening of channels to Cl− or K+ in postsynaptic cell

temporal summation

the input signals (EPSPs or IPSPs) arrive from the same presynaptic cell at different times

spatial summation

Although it clearly is necessary that stimulation of axons A and B occur closely in time for summation to occur, this is called spatial summation because the two inputs occurred at different locations on the cell.

->The interaction of multiple EPSPs through spatial and temporal summation can increase the inward flow of positive ions and bring the postsynaptic membrane to threshold so that action potentials are initiated

Study and Review 6.11

Temporal summation: summed potential created by more than one EPSP and/or IPSP arriving at a single synapse on a postsynaptic cell membrane in quick succession

Spatial summation: summed potential created by more than one EPSP and/or IPSP arriving together at different synapses on a postsynaptic cell membrane

Action potentials are generally initiated by the temporal and spatial summation of many EPSPs.

axo-axonic synapse

These presynaptic receptors may be associated with a second synaptic ending known as an axo-axonic synapse, in which an axon terminal of one neuron ends on an axon terminal of another.

presynaptic inhibition

Depending upon the type of presynaptic receptors activated by the neurotransmitter from neuron A, the presynaptic effect may decrease the amount of neurotransmitter released from B

presynaptic facilitation

Depending upon the type of presynaptic receptors activated by the neurotransmitter from neuron A, the presynaptic effect may increase the amount of neurotransmitter released from B

autoreceptors

Some receptors on the presynaptic terminal are not associated with axo-axonic synapses. Instead, they are activated by neurotransmitters or other chemical messengers released by nearby neurons or glia or even by the axon terminal itself. In the last case, the receptors are called autoreceptors (see Figure 6.33) and provide an important feedback mechanism that the neuron can use to regulate its own neurotransmitter output.

receptor desensitization

The ability of a given receptor to respond to its neurotransmitter can change. Thus, in some systems, a receptor responds normally when first exposed to a neurotransmitter but then eventually fails to respond despite the continued presence of the receptor's neurotransmitter, a phenomenon known as receptor desensitization.

->This is part of the reason that drug abusers sometimes develop a tolerance to drugs that elevate certain brain neurotransmitters, forcing them to take increasing amounts of the drug to get the desired effect

agonists

ligands that bind to a receptor and activate it are called agonists

antagonists

ligands that bind to a receptor and inhibit its activation are antagonists

tetanus toxin

the neurological disorder tetanus is caused by the bacillus Clostridium tetani, which produces a toxin (tetanus toxin).

This toxin is a protease that destroys SNARE proteins in the presynaptic terminal so that fusion of vesicles with the membrane is prevented, inhibiting neurotransmitter release.

botulism

food poisoning

Botox

Low doses of one type of botulinum toxin (Botox) are injected therapeutically to treat a number of conditions related to excessive muscle contractions, including facial wrinkles, uncontrollable blinking, migraine headaches, and others.

study and review 6.12

Synaptic strength: effectiveness of a synapse; can be modified pre- and postsynaptically

Presynaptic inhibition: inhibitory action produced by an axon terminal of one neuron directly on the terminal of another; results in less neurotransmitter release

Presynaptic facilitation: stimulatory action produced by the axon terminal of one neuron directly on the terminal of another; results in more neurotransmitter release

Postsynaptic alteration of synaptic strength may also occur, for example due to receptor desensitization.

Certain medications and diseases may alter synaptic strength by numerous mechanisms, including altering neurotransmitter synthesis, secretion, degradation, or reuptake.

neuromodulators

The word modulation is used for these complex responses, and the messengers that cause them are called neuromodulators

Acetylcholine (ACh)

Acetylcholine (ACh) is a major neurotransmitter in the PNS at the neuromuscular junction (where a motor neuron contacts a skeletal muscle cell; see Chapter 9) and in the brain.

Cholinergic

Neurons that release ACh are called cholinergic neurons.

acetylcholinesterase

After it is released and activates receptors on the postsynaptic membrane, the concentration of ACh at the postsynaptic membrane decreases (thereby stopping receptor activation) due to the action of the enzyme acetylcholinesterase.

-> This enzyme is located on the presynaptic and postsynaptic membranes and rapidly destroys ACh, releasing choline and acetate

Sarin

Some chemical weapons, such as the nerve gas Sarin, inhibit acetylcholinesterase, causing a buildup of ACh in the synaptic cleft.

nicotinic receptors

Some ACh receptors respond not only to acetylcholine but to the compound nicotine and have therefore come to be known as nicotinic receptors.

muscarinic receptor

The other general type of cholinergic receptor is stimulated not only by acetylcholine but by muscarine, a poison contained in some mushrooms; therefore, these are called muscarinic receptors.

-> These receptors are metabotropic and couple with G proteins, which then alter the activity of a number of different enzymes and ion channels.

Alzheimer's disease

Many cholinergic neurons in the brain degenerate in people with Alzheimer's disease, a brain disease that is usually age related and is the most common cause of declining intellectual function in late life

beta-amyloid protein

Mutations of genes on chromosomes 1, 14, and 21 are associated with abnormally increased concentrations of beta-amyloid protein, which is associated with neuronal cell death in a severe form of the disease that can begin as early as 30 years of age.

biogenic amines

small, charged molecules that are synthesized from amino acids and contain an amino group (R—NH2). The most common biogenic amines are dopamine, norepinephrine, serotonin, and histamine.

L-dopa

Synthesis of catecholamines begins with the uptake of tyrosine by the axon terminals and its conversion to another precursor, L-dihydroxyphenylalanine (L-dopa) by the rate-limiting enzyme in the pathway, tyrosine hydroxylase

dopamine, norepinephrine, epinephrine

all contain a catechol ring (a six-carbon ring with two adjacent hydroxyl groups) and an amine group, which is why they are called catecholamines

monoamine oxidase (MAO)

The catecholamine neurotransmitters are also broken down in both the extracellular fluid and the axon terminal by enzymes such as monoamine oxidase (MAO).

Monoamine Oxidase Inhibitors (MAOIs)

Drugs known as monoamine oxidase (MAO) inhibitors increase the amount of norepinephrine and dopamine in a synapse by slowing their metabolic degradation. Among other things, they are used in the treatment of mood disorders such as some types of depression.

alpha-adrenergic receptors

a class of adrenergic receptors that are further subdivided into alpha1 and alpha2 adrenergic receptors

-> 1 major class of receptors for norepinephrine and epinephrine

beta-adrenergic receptors

1 major class of receptors for norepinephrine and epinephrine

serotonin

is produced from tryptophan, an essential amino acid. Its effects generally have a slow onset, indicating that it works as a neuromodulator.

excitatory amino acids

aspartate, glutamate

glutamate

which is estimated to be the primary neurotransmitter at 50% of excitatory synapses in the CNS.

AMPA receptors

Although metabotropic glutamate receptors do exist, the vast majority are ionotropic, with two important subtypes being found in postsynaptic membranes. They are designated as AMPA receptors (identified by their binding to α-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid)

NMDA receptors

Although metabotropic glutamate receptors do exist, the vast majority are ionotropic, with two important subtypes being found in postsynaptic membranes. They are designated as NMDA receptors (which bind N-methyl-D-aspartate).

long-term potentiation (LTP)

Cooperative activity of AMPA and NMDA receptors has been implicated in one example of a synaptic modulation process called long-term potentiation (LTP).

Excitotoxicity

This is a phenomenon in which the injury or death of some brain cells (due, for example, to blocked or ruptured blood vessels) rapidly spreads to adjacent regions.

GABA (gamma-aminobutyric acid)

the major inhibitory neurotransmitter in the brain. Although it is not one of the 20 amino acids used to build proteins, it is classified with the amino acid neurotransmitters because it is a modified form of glutamate.

glycine

the major neurotransmitter released from inhibitory interneurons in the spinal cord and brainstem

neuropeptides

composed of two or more amino acids linked together by peptide bonds.

peptidergic

Neurons that release one or more of the peptide neurotransmitters are collectively called peptidergic

endogenous opioids

a group of neuropeptides that includes beta-endorphin, the dynorphins, and the enkephalins—have attracted much interest because their receptors are the sites of action of opiate drugs such as morphine and codeine.

nitric oxide

gas released by many small neurons; alters blood flow as well as neuronal activity

carbon monoxide and hydrogen sulfide

also emitted by neurons as signals

endocannabinoids N-arachidonoylethanolamine (anandamide)

The endocannabinoids are generated in response to Ca2+ entry into some postsynaptic cells and act as retrograde messengers by binding to specific receptors on presynaptic terminals.

Study and Review 6.13

In general, neurotransmitters cause EPSPs and IPSPs, and neuromodulators (such as certain neuropeptides) cause, via second messengers, more complex metabolic effects in a postsynaptic cell.

The actions of neurotransmitters are usually faster than those of neuromodulators.

A substance can act as a neurotransmitter at one type of receptor and as a neuromodulator at another.

Major classes of neurotransmitters:

-> acetylcholine

-> biogenic amines (including catecholamines and serotonin)

-> certain amino acids (e.g., glutamate, GABA, glycine)

-> gases including nitric oxide and hydrogen sulfide

-> neuropeptides (also act as neuromodulators; include the endogenous opioids)