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LECTURE 3 – NERVOUS SYSTEM PHYSIOLOGY
Synaptic transmission
Assoc. Prof. Ana-Maria Zagrean MD, PhD
Physiology & Neuroscience Div.
[email protected]
NEURONAL SYNAPSES
Neuroanatomist Santiago Ramón y Cajal (1894): neurons are distinct
entities, fundamental units of the nervous system, that are
discontinuous with each other.
Discontinuous neurons must nevertheless communicate, and Charles
Sherrington in 1897 proposed that the synapse, a specialized
apposition between cells, mediates the signals.
The word (chemical) synapse implies "contiguity, not continuity"
between neurons, as Cajal himself explained it.
At electrical synapses, which are less common than chemical
synapses, the membranes remain distinct, but ions and other small
solutes can diffuse through the gap junctions, a form of continuity.
The fine structure of synapses was finally revealed with the electron
microscope in the 1950s.
SYNAPTIC TRANSMISSION
Synaptic functions of neurons
How is information transferred from one neuron to another?
Types of synapses:
Electrical synapses
Chemical synapses
Volume transmission
Chemical synapses
Mechanism of transmitter release from the presynaptic terminals
Action of the transmitter substance on the postsynaptic neuron
Membrane potential of neuronal soma - postsynaptic potentials
Excitation (EPSP)
Inhibition (IPSP)
Synaptic functions of neurons
Information  Action potentials / Nerve impulses
transmission through a succession of neurons, that can be:
(1) blocked from one neuron to the next,
(2) changed from a single impulse into repetitive impulses,
(3) integrated with impulses from other neurons to cause highly
intricate patterns of impulses in successive neurons.
Types of synapses
(1) ELECTRICAL SYNAPSE
(2) CHEMICAL SYNAPSE
(3) VOLUME TRANSMISSION…
Types of synapses
(1) ELECTRICAL SYNAPSE
- Only a few examples of gap junctions found in the central nervous
system, comparing with their distribution in smooth or cardiac
muscle fibres
- characterized by direct open fluid channels - gap junctions, that
directly conduct electricity from one cell to the next; no time delay
- transmit signals in either direction with equal efficiency
(bidirectional/reciprocal synapses).
(2) CHEMICAL SYNAPSE
(3) VOLUME TRANSMISSION…
Types of synapses
(1) ELECTRICAL SYNAPSE
(2) CHEMICAL SYNAPSE
- most of the synapses used in the CNS for signal transmission
- the first neuron (presynaptic) secretes at its nerve ending a
chemical substance – neurotransmitter / transmitter substance, that
diffuses into the synaptic cleft to act on receptor proteins in the
membrane of the next neuron (postsynaptic) to excite it, inhibit it, or
modify its sensitivity
- > 40 neurotransmitters discovered thus far, most known are:
acetylcholine, norepinephrine, epinephrine, histamine, gammaaminobutyric acid (GABA), glycine, serotonin, glutamate.
- “one-way” conduction at chemical synapses, from the presynaptic
to postsynaptic neuron, allows specific transmission of signals
toward specific goals, to discrete and highly focused areas both
within the nervous system and at the terminals of the peripheral
nerves, to perform its myriad functions of sensation, motor control,
memory; synaptic delay.
(3) VOLUME TRANSMISSION…
Types of Synapses: What are the differences?
Electrical Synapses
Chemical Synapses
Both types of synapses can coexist on the same neuron…
Electrical synapse : GAP junctions
- extremely fast and limited only by the time constants of the systems involved,
- use relatively little metabolic energy or molecular machinery,
- observed (by expression of Cx36) in nearly every part of the mammalian CNS:
interconnect inhibitory neurons of the cerebral cortex and thalamus,
excitatory neurons of the brainstem, and a variety of other neurons in the
hypothalamus, basal ganglia, and spinal cord.
Electrical synapse : GAP junctions
-Facilitates fast transmission of current between
neighbouring cells, but potential decays with
distance
-Direct flow of current, no synaptic delay
-Both directions transmission, but certain
electrical synapses with voltage-dependent
gates conduct more readily in one direction
than in another
-Also transmit metabolic signals between cells
-Connexon channels (2 connexons of the
coupled cells, with a 1.5 nm pore) open and
close randomly, with a higher probability to
open when there is an elevated level of
intracellular Ca2+ or H+ in one of the cells, or
in response to depolariz. of one or both cells
Connect both neurons and glial cells (neuronal and
glial cells networks):
 typically found in dendro-dendritic sites to synchronize
the activity of neuronal populations
more common in embryonic nervous system  help the
development of appropriate synaptic connections based on
synchronous firing of neuronal populations.
Chemical synaptic transmission
CNS synapse
Neuronal synapses vary widely in the size of the synaptic
contact, the identity of the neurotransmitter, the nature of the
postsynaptic receptors, the efficiency of synaptic transmission,
the mechanism used for terminating transmitter action, and the
degree and modes of synaptic plasticity.
Thus, the properties of neuronal synapses can be tuned to
achieve the diverse functions of the brain.
PNS synapse
The most common synaptic arrangements in the CNS
In >90% of all excitatory
synapses in the CNS, the
postsynaptic site is a
dendritic spine.
The contact site and direction of
communication determine the way in
which a synapse is named:
axodendritic/ axospinous,
axosomatic, and axoaxonic
synapses.
Also, dendrodendritic, somatosomatic, and even somato-dendritic
synapses may be found in the
mammalian brain.
A, Drawings of various dendrites in the
neocortex, taken from Golgi-stained material.
The numerous protrusions are "spines."
B, Electron micrograph of an axospinous
synapse in the neocortex.
-The ubiquity of spines implies that they serve prominent functions, but their small size
(usually less than 1 μm long) makes their function extremely difficult to study.
-Spines’ density and shape vary  neuroplasticity.
-Spines contain more than 30 proteins in high concentration, including transmitter
receptors, protein kinases, a multitude of structural proteins, and proteins that are
involved in endocytosis and glycolysis.
Spiny dendrites from hippocampal pyramidal neuron.
Left: Light microscope image. Right: Reconstruction from serial electron
microscopy.
http://synapses.clm.utexas.edu/anatomy/dendrite/dendrite.stm#spines
Chemical Synapses
-structure:
1. Presynaptic terminal (end feet/axon knob)
2. Synaptic cleft (~20-30 nm, isolation by glial cells)
3. Postsynaptic membrane
-function:
-depends on neurotransmitters
-unidirectional signal transmission
discrete & directed towards specific goals
When AP spreads over a presynaptic
terminal depolarization of its
membrane  small number of vesicles
empty the transmitter into the cleft 
transmitter-postsynaptic receptor
interaction change in permeability of
the postsynaptic neuronal membrane
excitation OR inhibition of the
postsynaptic neuron, depending on the
neuronal receptor characteristics
CHEMICAL SYNAPSE
Neurotransmitters, Vesicles, Receptors
Physiologic Anatomy of the Synapse
Anterior motor neuron (anterior horn of the
spinal cord):
- Soma
- One single axon – extends into a peripheral
nerve
- Dendrites – projects up to 1 mm into the
surrounding areas of the cord
-no. of presynaptic terminals/neuron: from a few up to 10,000-200,000 on
the soma of the motor neuron, from which ~80-95% lie on the dendrites and
only 5–20% on the soma
Presynaptic terminals
(axon boutons, end-feet, or synaptic knobs)
-Presynaptic terminals contain transmitter vesicles and
mitochondria
-AP at presynaptic level open voltage-gated Ca channels 
[Ca2+]i increases  transmitter release from the vesicles
(exocytosis) chemical transmission
-vesicles with Ach store 2,000-10,000 molec./vesicle; there are
enough vesicles to transmit >10,000 APs.
-presynaptic terminals contain enzymes for synthesis of smallmolecule /nonpeptide transmitters from simple precursors;
-the neuropeptides are synthesized in the soma RER, packed in
vesicles  axonal transport presynaptic terminal.
Presynaptic terminals
Autoreceptors
Presynaptic
Postsynaptic
Norepinephrine
autoreceptor
Receptors located presynaptically
Modulate presynaptic neuronal activity
Receptor on the same neuron that makes the transmitter (thus auto…)
Chemical synapses:
Postsynaptic segment
The transmitter molecules once released bind and influence the membrane
potential of the postsynaptic membrane, determining excitation or inhibition
The postsynaptic membrane has receptor proteins with 2 components:
• A binding component/sites for ligands/neurotransmitters
• An ionophore component that passes all the way through the
postsynaptic membrane to the interior of the postsynaptic neuron, that
can be one of 2 types:
1. an ion channel: excitatory (allows Na+ entry)
inhibitory (allows negative charge to enter)
2. a second messenger activator – a molecule that protrudes into
the cell cytoplasm and activates one or more "second
messengers" to increase or decrease specific cellular functions.
Chemical synapse transmission occurs in 7 steps
Step 1: Neurotransmitter molecules are packaged into membranous vesicles, and the
vesicles are concentrated and docked at the active zones / release sites of the
presynaptic terminal.
Step 2: The presynaptic membrane depolarizes, usually as the result of an AP
Step 3: The depolarization causes voltage-gated Ca2+ channels to open and allows
Ca2+ ions to flow into the terminal.
Step 4: The resulting increase in intracellular [Ca2+] triggers fusion of vesicles with
the presynaptic membrane. The Ca2+ dependence of fusion may be conferred by a
neuron-specific protein component of the fusion apparatus called synaptotagmin. The
actual fusion events are incredibly fast; each individual exocytosis requires only a
fraction of a msec. to be completed.
Chemical synapse transmission occurs in 7 steps
Step 5: The transmitter is released into the extracellular space in quantized
amounts and diffuses passively across the synaptic cleft (20-30 nm thick).
Step 6: Some of the transmitter molecules bind to receptors in the
postsynaptic membrane, and the activated receptors trigger some
postsynaptic event, usually the opening of an ion channel (fast synapse) or the
activation of a G protein-coupled signal cascade (slow synapse).
Step 7: Transmitter molecules diffuse away from postsynaptic receptors and
are eventually cleared away by continued diffusion, enzymatic degradation,
or active uptake into cells. In addition, the presynaptic machinery retrieves the
membrane of the exocytosed synaptic vesicle, perhaps by endocytosis from
the cell surface.
Mechanism of transmitter release
Synaptic transmission at a chemical synapse can be thought of as occurring in 7 steps
Why are some
postsynaptic receptors
excitatory while others
are inhibitory?
Transmitter evokes
membrane depolarization
or hyperpolarization
 Excitatory / inhibitory
transmitters
Why are some Postsynaptic Receptors excitatory while
others are inhibitory?
Excitation
• Opening of Na+ channels
Raises membrane potential closer to threshold
• Depressed conduction of Cl- or K+
Internal membrane potential becomes more positive
• Changes in the internal metabolism of the postsynaptic neuron
Excitatory Postsynaptic Potentials (EPSPs)
•Occur when:
• Na+ and/or Ca2+ channels open,
OR
• K+ and /or Cl- channels close
•Cation influx or reduced K+ efflux causes the membrane to
become depolarized
Why are some Postsynaptic Receptors
excitatory while others are inhibitory?
Inhibition
Open Cl- or K+ channels
• Membrane hyperpolarization
• Inhibit cellular metabolic functions …
Inhibitory Postsynaptic Potentials (IPSPs)
Occur when:
• Cl- channels open
OR
• K+ channels open
Cl- influx or K+ efflux ensues and the membrane becomes
hyperpolarized, i.e., membrane potential becomes lower than Vrest
 more energy is required to achieve threshold.
Electrical Events During Neuronal Excitation
Three states of a neuron. A, Resting neuron, with a normal intraneuronal potential of -65 mV.
B, Neuron in an excited state, with a less negative intraneuronal potential (-45 mV) caused by
sodium influx. C, Neuron in an inhibited state, with a more negative intraneuronal membrane
potential (-70 mV) caused by potassium ion efflux, chloride ion influx, or both.
Postsynaptic mechanisms
There are several types of second messenger systems in the postsynaptic neuron.
One of the most prevailing types in neurons, G-protein (with ,  &  components), is
attached to the portion of the receptor protein that protrudes to the interior of the cell.
G-protein activation: a nerve impulse activates the  activator portion of the G-prot
and separates it from the  and  portions, then moves free within the cell cytoplasm.
Postsynaptic mechanisms
G-proteins system
Inside the cytoplasm, the separated alpha component (G) performs one or
more of multiple functions, depending on the specific characteristic of each
type of neuron:
• Opening specific ion channels through the postsynaptic cell membrane.
These channels often stay open for a prolonged time.
• Activation of cyclic adenosine monophosphate (cAMP) or cyclic
guanosine monophosphate (cGMP) in the neuronal cell.
• Activation of one or more intracellular enzymes. In turn the enzymes can
cause any one of many specific chemical functions in the cell.
• Activation of gene transcription…
 Prolonged and amplified response
Amplification. A, One neurotransmitter (NT) binds directly to a channel, thereby activating it.
B, One NT binds to a receptor that in turn activates 10 - 20 G proteins. In this example, the β
subunits directly activate K+ channels. In addition, each activated α subunit activates an adenylyl
cyclase (AC) molecule, each of which produces many cAMP molecules that activate protein
kinase A (PKA). C, Each activated PKA can phosphorylate and thereby modulate many channels.
Control of transmitter activity in synaptic cleft
In two ways:
• Reuptake by presynaptic cell
• Deactivation in the synaptic cleft
Reuptake
•Norepinephrine and glutamate are taken up into the presynaptic cell.
•Glutamate is taken through Na+-linked transport, both into neurons and
astrocytes.
Deactivation
• Acetylcholine is digested by cholinesterase
• Norepinephrine is deactivated by methylation by catechol-O methyl
transferase (COMT) and cleared into the blood circulation.
•Neuropeptides action is terminated by proteolysis or by diffusion away from
the postsynaptic membrane
Vesicle Re-uptake
Within seconds to minutes of exocytosis, the vesicle portion of the membrane
invaginates back to the inside of the presynaptic terminal and pinches off to
form a new vesicle.
The new vesicle still contains the appropriate transport proteins required for
synthesizing and for concentrating new transmitter substance inside it.
Glial presence at synaptic level
– astrocytes do not fire action potentials, but are Ca2+-excitable!
– one astrocyte contacts 1000s of synapses !!!
– astrocytes ‘listen’ to neurons (all major receptors present on astrocytes)
– astrocytes release neurotransmitters (Glu, ATP, …)
– astrocytes modulate neuronal excitability and synaptic transmission
The “One-Neuron-One-Messenger” Dogma
It was previously believed that any given synaptic terminal releases one and
only one transmitter substance, which is characteristic of that kind of
synapse. This belief has been discredited.
Current Evidence:
•Multiple chemical messengers co-exist in single nerve cells
As a rule, small transmitters are stored and released by separate sets of
neurons. The peptides, however, are usually stored and released from the same
neurons as one of the small transmitters (co-localization of neurotransmitters).
•Transmitter substances can be both excitatory and inhibitory, as the
postsynaptic response is determined by the nature of postsynaptic
receptor .
Neuroactive peptides co-localize with small-molecule neurotransmitters
Small Molecule
Acetylcholine
Dopamine
Epinephrine
GABA
Glutamate
Glycine
Norepinephrine
Serotonin
Co-localized Peptide(s)
Enkephalin, Vasoactive intestinal polypeptide
Calcitonin gene-related peptide
Substance P, Somatostatin and enkephalin
Gonadotropin-releasing hormone
Neurotensin, Galanin
Cholecystokinin, Enkephalin
Neurotensin
Enkephalin, Neuropeptide Y
Neurotensin, Substance P
Cholecystokinin, Enkephalin
Somatostatin, Neuropeptide Y
Substance P, Vasoactive intestinal polypeptide
Substance P
Neurotensin
Enkephalin, Neuropeptide Y
Neurotensin, Somatostatin
Vasopressin
Cholecystokinin, Enkephalin
Substance P and thyrotropin-releasing hormone
Thyrotropin-releasing hormone
Fast Chemical Synapses
In fast chemical synapses:
-Neurotransmitter is synthesized in the presynaptic terminal
-Neurotransmitter molecules are small, eg, acetylcholine, GABA
-Storage is in small vesicles
-Vesicles are located near plasma membrane (active zones)
Slow Chemical Synapses
In slow chemical synapses:
•Transmitter molecules are large, e.g., peptides, amines
•Storage is in large, dense vesicles
•Vesicles are located further away from the terminal
•Release sites are to the side of the terminal
1 Na+
Ach
Fast
Synapses
Ligand-gated
ion channel
2
example- nicotinic AchR
stimulates by Na+ influx
3
Ach
1
Intermediate
Membrane delimited signaling
through G protein
22
G
NE
3
K+
1
example- muscarinic AchR
inhibits the heart by activating
K+ channels
Ca2+
Slow
2
G
3
G-protein signaling through
4
intracellular second messenger cascade
example- -adrenergic receptor
stimulates the heart by modulating
Ca2+ channels
PO
4
5
Time courses of synaptic events in the nervous system.
Different transmitter systems in the brain generate responses that vary widely in
how long they last in the postsynaptic cell, from a few milliseconds to hours and
days. Note that the time axis is logarithmic. (Data from Shepherd GM: Neurobiology,
3rd ed. New York: Oxford University Press, 1994.)
Divergence and convergence of transmitter
effects on ion channels.
A, One transmitter, norepinephrine in this case,
can activate multiple receptors, which stimulate
different G protein/second messengers, which in
turn either stimulate or depress the gating of
many types of ion channels.
IAHP stands for afterhyperpolarization current, which is
mediated by a Ca2+-activated K+ channel. Ih stands for
hyperpolarization-activated cation current.
B, Multiple transmitters bind to their specific
receptors and, by the same or different secondmessenger systems, influence the same set of
ion channels.
ACh, acetylcholine; DA, dopamine; Enk, enkephalin;
5-HT, 5-hydroxytryptamine (serotonin);
NE, norepinephrine; SS, somatostatin;
SSTR, somatostatin receptor.
Synaptic connections/networks.
The brain carries out many sensory, motor, and
cognitive functions that require fast, specific,
spatially organized neural connections and
operations (such as the detailed neural mapping
allowing you to read this sentence).
Require spatially focused networks.
Falling asleep, waking up, attention or changing mood
involve more general changes in the brain. Several
systems of neurons regulate the general excitability of
the CNS, each of these modulatory systems uses a
different neurotransmitter, and the axons of each
make widely dispersed, diffuse, almost meandering
synaptic connections to carry a simple message to
vast regions of the brain.
Require widely divergent network.
Synaptic connections/networks.
Some transmitters are used by diffusely distributed systems of neurons to
modulate the general excitability of the brain.
Modulatory systems use different neurotransmitters, in widely dispersed, diffuse,
almost meandering synaptic connections to carry a simple message to vast regions of
the brain (widely divergent networks).
The functions of the different systems are not well understood, but each appears to be
essential for certain aspects of arousal, motor control, memory, mood, motivation, and
metabolic state.
The brain has several modulatory systems with diffuse central connections:
1. Neurons of the diffuse systems arise from the central core of the brain, most of
them from the brainstem !!! (typically, several thousand)
2. Each neuron can influence many others because each one has an axon that may
contact more than 100,000 postsynaptic neurons spread widely across the brain.
3. The synapses made by some of these systems seem designed to release
transmitter molecules into the extracellular fluid so that they can diffuse to many
neurons rather than be confined to the vicinity of a single synaptic cleft – volume
transmission.
Synaptic connections/networks.
The main modulatory systems of the brain are distinct anatomically and
biochemically.
Separate systems use norepinephrine, serotonin (5-hydroxytryptamine [5-HT]),
dopamine, ACh, or histamine as their neurotransmitter.
They all tend to involve numerous metabotropic transmitter receptors. Unlike
ionotropic receptors, which are themselves channels, metabotropic receptors are
coupled to enzymes such as adenylyl cyclase or phospholipase C through G
proteins
For example, the brain has 10 to 100 times more metabotropic (i.e., muscarinic)
ACh receptors than ionotropic (i.e., nicotinic) ACh receptors.
Collectively, the diffuse modulatory systems may be viewed as general
regulators of brain function, much like the autonomic nervous
system regulates the organ systems of the body. Because their
axons spread so widely within the CNS, the few modulatory
neurons can have an inordinately strong influence on behavior.
The four diffusely
connected systems of
central neurons using
modulatory transmitters:
Ach, NE, Dopamine,
Serotonin
Chemical Substances That Function as Synaptic Transmitters:
Neurotransmitters and Neuromodulators
No chemical distinction between neurotransmitters and
neuromodulators.
A neurotransmitter stimulate the primary postsynaptic
response
•Is released during activity of presynaptic neuron
•Effects on postsynaptic cell and on the presynaptic cell
•Action at synapse is blocked by antagonists
Neuromodulators modify the primary synaptic response. May
act on neighboring neurons.
Small-molec., rapidly acting / neuropeptides, slowly acting
e.g., transmission of sensory signals to
the brain and of motor signals back to
the muscles.
long-term changes in number of neuronal
receptors, long-term opening/closure of certain
ion channels, possibly even long-term changes
in number or sizes of synapses.
Neurotransmitters: intercellular messenger molecule
CONVENTIONAL NEUROTRANSMITTERS (stored in synaptic vesicles [SV] and
released in quantal fashion by Ca2+ dependent exocytosis)
Small-Molecule, Rapidly Acting Transmitters
Acetylcholine
Released at
Amino Acids
classical synapses,
Gamma-aminobutyric acid (GABA), Glycine, Glutamate, Aspartate
wiring transmission
Purines:
ATP, Adenosine
Amines Released both at classical synapses (wiring transmission), but also at
en passant synapses – SV varicosities along axons as they pass postsynaptic
cells (e.g. sympathetic neuron – smooth mm cell; volume transmission).
Catecholamines: Norepinephrine, Epinephrine, Dopamine (all derived from tyrosine)
Serotonin
Histamine
Neuropeptide, Slowly Acting Transmitters or Growth Factors
UNCONVENTIONAL NEUROTRANSMITTERS (not stored in synaptic vesicles, lipidsoluble)
Gaseous transmitters
Nitric oxide (NO), Carbon monoxide (CO)
Lipids – endogenous endocannabinods (2-arachidonoylglycerol)
Neuropeptide, Slowly Acting Transmitters
Peptides that act on gut and brain
Hypothalamic-releasing hormones
Leucine enkephalin
Thyrotropin-releasing hormone
Luteinizing hormone-releasing hormone Methionine enkephalin
Somatostatin (growth hormone inhibitory Substance P
Gastrin
factor)
Cholecystokinin
Vasoactive intestinal polypeptide (VIP)
Pituitary peptides
Nerve growth factor
Adrenocorticotropic hormone (ACTH)
Brain-derived neurotropic factor
β-Endorphin
Neurotensin
α-Melanocyte-stimulating hormone
Insulin
Prolactin
Glucagon
Luteinizing hormone
Thyrotropin
From other tissues
Growth hormone
Angiotensin II
Vasopressin
Bradykinin
Oxytocin
Sleep peptides
Calcitonin
ACh - ester of acetic acid and choline: CH3COOCH2CH2N+(CH3)3
Acetylcholine (ACh)
-first neurotransmitter to be identified in 1914 by H. H. Dale for its actions on
heart tissue; confirmed as a neurotransmitter by Otto Loewi who initially gave
it the name vagusstoff because it was released from the vagus nerve (1936
Nobel Prize in Physiology or Medicine).
-synthesized in the presynaptic terminal from acetyl coenzyme A and choline
in the presence of the enzyme choline acetyltransferase, and transported
into its specific vesicles.
-released into the synaptic cleft where is rapidly split to acetate and choline
by the enzyme cholinesterase from the proteoglycan reticulum.
-choline is actively transported back into the presynaptic terminal to be used
again for synthesis of new acetylcholine.
Acetylcholine secreting neurons:
(1) large pyramidal cells from the motor cortex,
(2) neurons in the basal ganglia,
(3) motor neurons innervating skeletal muscles,
(4) the preganglionic neurons of the autonomic nervous system,
(5) the postganglionic neurons of the parasympathetic nervous system
(6) some postganglionic neurons of the sympathetic nervous system.
Acetylcholine receptors:
Ionotropic nicotinic receptors (neuromuscular junction)
Metabotropic muscarinic receptors (cardiac muscle)
ach
ach
Nicotinic
Muscarinic
EPSP
IPSP
Acetylcholine effects:
In most instances ACh has an excitatory effect; however, it is known to
have inhibitory effects at some peripheral PS nerve endings (inhibition
of the heart by the vagus nerves).
Neurons containing ACh are located in the basal forebrain complex, which includes
the septal nuclei and nucleus basalis; the neurons project to the hippocampus and
the neocortex. Other ACh-containing neurons originate in the
pontomesencephalotegmental cholinergic complex and project to the dorsal
thalamus and part of the forebrain.
Ionotropic and metabotropic
ACh receptors.
A - nicotinic AChR: ligandgated channel on the
postsynaptic membrane. In a
skeletal muscle, the end result
is muscle contraction.
B - muscarinic AChR, which is
coupled to a G protein. In a
cardiac muscle, the end result
is decreased heart rate.
Same presynaptic release of
ACh is similar here and in A.
Norepinephrine
-secreted by
the terminals of many neurons whose cell bodies are located in
the hypothalamus and brain stem:
locus ceruleus in the pons send nerve fibers to widespread areas
of the brain  control overall activity and mood (e.g., increasing the
level of wakefulness).
most postganglionic neurons of the sympathetic nervous
system, where it excites some organs or inhibits others.
-mostly excitatory effects, but also inhibitory, depending on the type of
receptors:
Receptor Type
Agonists*
Antagonists
G
Second
Protein Linked Enzyme Messenger
α2-Adrenergic
NE ≥ Epi (clonidine)
Yohimbine
Gαi
Adenylyl cylase ↓ [cAMP]i
β1-Adrenergic
Epi > NE (dobutamine,
isoproterenol)
Epi > NE (terbutaline,
isoproterenol)
Metoprolol
Gαs
↑ [cAMP]i
Butoxamine
Gαs
Adenylyl
cyclase
Adenylyl
cyclase
Adenylyl
cyclase
↑ [cAMP]i
β2-Adrenergic
β3-Adrenergic
Epi > NE (isoproterenol) SR-59230A
Gαs
↑ [cAMP]i
Neurons containing NE are located in the locus coeruleus and
innervate nearly every part of the CNS
Dopamine
- secreted by neurons that originate in the substantia nigra.
-the termination of these neurons is mainly in the striatal region of the
basal ganglia.
-effect s of dopamine: usually inhibition, but also excitation.
-dopamine receptors:
Receptor
Type
Agonists*
D1
Dopamine
D2
Dopamine
Second
Antagonists G Protein Linked Enzyme Messenger
Gαs
Adenylyl
↑ [cAMP]i
cyclase
Gαi
Adenylyl
↓ [cAMP]i
cyclase
Neurons containing dopamine are located in the substantia nigra (and these
project to the striatum) and the ventral tegmental area of the midbrain (and
these project to the prefrontal cortex and parts of the limbic system).
Glycine
-secreted mainly at synapses in the spinal cord.
-act as an inhibitory transmitter.
-also, influence NMDA receptor activity.
Renshaw Cell and Glycine - Major inhibitory transmitter in the spinal cord
skeletal muscle:
Spinal cord:
Ach (+)
glycine
(-)
Ach
(+)
Renshaw Interneuron
Serotonin (5-hydroxytryptamine, 5-HT)
-secreted by nuclei that originate in the median raphe of the brain stem
and project to many brain and spinal cord areas, especially to the
dorsal horns of the spinal cord and to the hypothalamus.
-acts as an inhibitor of pain pathways in the cord, and an inhibitor
action in the higher regions of the nervous system;
-is believed to help control the mood of the person, perhaps even to
cause sleep.
-Serotonine receptors: G protein-coupled receptors and ligand-gated
ion channels (only 5-HT3) found in the central and peripheral nervous
system, mediating both excitatory and inhibitory neurotransmission.
Serotonine
Receptor Family
5-HT1
5-HT2
5-HT3
5-HT4
5-HT5
5-HT6
5-HT7
Type
Mechanism
Potential
Gi/Go-protein
coupled.
Gq/G11-protein
coupled.
Ligand-gated
Na+ and K+
cation channel.
Gs-protein
coupled.
Gi/Go-protein
coupled.
Gs-protein
coupled.
Gs-protein
coupled.
↓ cAMP
Inhibitory
↑ IP3 and DAG.
Excitatory
Depolarizing plasma
Excitatory
membrane
↑ cAMP.
Excitatory
↓ cAMP.
Inhibitory
↑ cAMP.
Excitatory
↑ cAMP.
Excitatory
Neurons containing serotonin are located in two
groups of raphe nuclei and project to most of the brain.
Glutamate
-excitatory aminoacid / neurotransmitter
-secreted by the presynaptic terminals in many of the sensory pathways
entering the central nervous system, as well as in many areas of the
cerebral cortex.
-Glutamate receptors:
-ionotropic
NMDA rec. (N-methyl D-aspartate)
AMPA/quisqualat rec.
(AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
Kainic ac. rec.
(KA - natural marine acid present in some seaweed)
-metabotropic mGluR I & II
-Involved in:
– Memory & learning
– Synapse formation
– Pathological states (excess glutamate):
epilepsy, Parkinson’s and Alzheimer's disease, stroke, trauma and hypoxia
Glutamate-gated channels.
A, At most glutamate-mediated synapses,
the EPSP (red curve) is the sum of two
components (1) a rapid component that is
mediated by an AMPA receptor channel
(green) and (2) a slow component that is
mediated by an NMDA receptor channel
(orange); here postsynaptic Vm is
relatively negative, the contribution of
the NMDA rec. channel is very small.
B, At a relatively negative initial Vm in
the postsynaptic cell, as in A, the NMDA
receptor channel does not open. The
AMPA receptor channel, which is indep.
of postsynaptic Vm, opens. The result is a
fast depolarization. C, In this example, in
which the postsynaptic Vm is relatively
positive, the contribution of the NMDA
receptor channel is fairly large. D, At a
relatively positive initial Vm in the
postsynaptic cell, as in C, glutamate
activates both the AMPA and the NMDA
receptor channels. The recruitment of the
NMDA receptor channels is important
because unlike most AMPA receptor
channels, they allow the entry of Ca2+
and have slower kinetics.
GABA (gamma-aminobutyric acid)
-most abundant endogenous inhibitory neurotransmitter
-secreted by nerve terminals in the spinal cord, cerebellum, basal
ganglia, hippocampus and many areas of the cortex.
-GABA receptors: found in most of the CNS neurons (60-80%)
GABA A – ionotropic ligand gated receptors (open Cl- channels)
binding sites for benzodiazepines (diazepam), barbiturates
GABA B – metabotropic G-protein coupled receptors
(open K+ channels or suppress Ca2+ channels).
-GABA antagonist: Bicucculine, gabazine
-GABA agonists: selective for GABA A Rec - Muscimol, isoguvacine
selective for GABA B Rec - L-baclofen
- in mature neurons facilitate hyperpolarization of the cell by gating
chloride ions in the interior of the nerve cell (!)
-prevent firing of presynaptic neurotransmitters (presynaptic inhibition)
-depress CNS activity, keep the excitatory-inhibitory balance…
GABAA receptor channel
- GABA binding site
- several other sites on the outside face of the receptor, where modulator chemicals
can bind: benzodiazepines (diazepam [Valium]) and barbiturates (phenobarbital)
Alone, these drugs do very little to the channel's activity, but in the presence of
GABA, benzodiazepines increase the frequency of channel opening and
increase Cl- conductance, whereas barbiturates increase the duration of
channel opening.
more inhibitory Cl- current, stronger IPSPs, and the behavioral
consequences of enhanced inhibition.
N.B. during development GABA A rec. is excitatory, due to increased intracellular Clconcentration  Cl- efflux  EPSP
? what endogenous ligands/natural chemicals exist for benzodiazepines/barbiturates
- various metabolites of the steroid hormones progesterone, corticosterone, and
testosterone, increase the lifetime or opening frequency of GABA-activated singlechannel currents, enhance inhibition, and therefore are potential natural modulators of
the GABAA receptor
- steroid hormones modulate GABAA receptor through distinct binding sites…
The GABAA receptor is also subject to modulation by the effects of phosphorylation
triggered by second-messenger signaling pathways within neurons.
GABAA receptor channel.
A, a pulse of GABA released elicits a
small IPSP.
B, In the presence of a low dose of
pentobarbital, the pulse of synaptic
GABA elicits a much larger IPSP 
barbiturate enhances inhibition.
C, At the single-channel level, GABA by
itself elicits brief channel openings.
D, Barbiturate (here 50 μM pentobarbital)
does not by itself activate the GABAA
receptor channel but increases the
channel open time when GABA is
present.
E, The channel receptor is a heteropentamer. It not only has a pore for Cl- but
also has separate binding sites for GABA
and several classes of channel
modulators.
The inset shows the presumed structure of one
of the 5 monomers. The M2 do-main of each of
the 5 subunits presumably lines the central
channel pore.
Nitric oxide
-short-lived gas, that diffuses a short distance to neighboring cells, where its effects
are primarily mediated by the activation of guanylyl cyclase (GC).
-first identified as endothelium-derived relaxation factor (EDRF)
-a nonconventional transmitter system that may be involved in behavior and
memory functions
- different from other small-molecule transmitters in its mechanism of formation in the
presynaptic terminal and in its actions on the postsynaptic neuron:
-is not preformed and stored in vesicles in the presynaptic terminal as are other
transmitters.
-is synthesized almost instantly as needed, and it then diffuses out of the
presynaptic terminals over a period of seconds
-diffuses into postsynaptic neurons nearby, where does not greatly alter the
membrane potential but instead changes intracellular metabolic functions that
modify neuronal excitability for seconds, minutes, or perhaps even longer.
-abnormalities of the NO system are involved in the pathophysiological processes of
adult respiratory distress syndrome, high-altitude pulmonary edema, stroke, and
other diseases introduction of clinical treatments that modulate the NO system
(use of gaseous NO for treatment of pulmonary edema, NO generators such as
nitroglycerin for treatment of angina, and cGMP phosphodiesterase inhibitors such
as sildenafil (Viagra) for treatment of erectile dysfunction).
Neuropeptides
• widespread in both CNS and PNS
• excitatory and inhibitory
• act as hormones elsewhere in the body
-Substance P -- enhances our perception of pain
-Opioid peptides:
endorphins - released during stress, exercise
-breaks down bradykinins (pain chemicals), boosts
the immune system and slows the growth of cancer cells
-binds to mu-opioid receptors
-released by the hypothalamic neurons and by the cells
of the pituitary
enkephalins - analgesics
-breaks down bradykinins (200x stronger than morphine)
-pain-relieving effect by blocking the release of substance P
dynorphins - regulates pain and emotions
PRESYNAPTIC INHIBITION
•inhibitory fiber (usually GABAergic) connects with presynaptic excitatory
knob  presynaptic hyperpolarization reduced transmitter release
reduced postsynaptic potential (PSP).
• imparts the property of high selectivity - it affects only signals arriving at
that particular synapse.
• works by subtracting from all excitatory PSPs that arrive at the neuron 
nonselective inhibition.
• increases both the specificity and the complexity of the integration
that takes place at the neuronal level.
• Presynaptic inhibition occurs in many of the sensory pathways in the
nervous system
! Adjacent sensory nerve fibers often mutually inhibit one another, which
minimizes sideways spread and mixing of signals in sensory tracts.
Excitatory postsynaptic potentials (EPSP): simultaneous firing of only a few
synapses will not cause sufficient summated potential to elicit an action potential,
but that simultaneous firing of many synapses will raise the summated potential to
threshold for excitation and cause a superimposed action potential.
SUMMATION
Transmitter substance released by a single presynaptic
terminal cause an EPSP usually no greater than 0.5 to 1 mV,
instead of the 10-20 mV normally required to reach threshold
for excitation, but many presynaptic terminals are usually
stimulated at the same time  summation
Postsynaptic potentials (PSP) originating from the same or
neighboring synapses can summate.
Depending on the synapse(s) of origin, there are spatial or
temporal summation.
Spatial Summation (in space)
• Postsynaptic potentials (PSPs)
originate from different synapses
• PSPs spread easily because of the low
resistance of soma membrane
• If an EPSP, the membrane potential is
elevated in neighboring area. Facilitation
occurs. Thus a smaller voltage change is
required to reach threshold in the
neighboring area.
• If an IPSP, the reverse occurs.
• EPSPs can summate with IPSPs and
diminish the size of the summated
potential.
The effect of summing simultaneous
postsynaptic potentials by activating
multiple terminals on widely spaced
areas of the neuronal membrane is
called spatial summation.
Temporal Summation (in time)
Successive discharges from a
single presynaptic terminal
occurring rapidly enough, can add to
one another = “temporal summation“.
Postsynaptic potentials decay slowly.
Because of the slow decay of a prior
PSP, a second PSP may arrive at the
same synapse before the initial one
has decayed.
This allows PSPs to summate.
Temporal Summation (in time)
Summation is dependent on impulse
frequency, i.e., is frequency modulated.
The higher the frequency, the greater
the summation and the greater the
potential.
EPSPs combine to cause an AP.
IPSPs combine to cause greater
hyperpolarization, making an AP less
likely.
The effects of spatial and temporal
summation are additive.
Spatial versus temporal summation of excitatory postsynaptic potentials (EPSPs).
Some Special Characteristics of Synaptic Transmission
Fatigue of Synaptic Transmission:
When excitatory synapses are repetitively stimulated at a rapid rate, the number of
discharges by the postsynaptic neuron is at first very great, but the firing rate
becomes progressively less in succeeding millisec. or seconds.
Fatigue is an exceedingly important characteristic of synaptic function because
when areas of the nervous system become overexcited, fatigue causes them to
lose this excess excitability after a while.
Fatigue is probably the most important means by which the excess excitability of
the brain during an epileptic seizure is finally subdued so that the seizure ceases the development of fatigue is a protective mechanism against excess
neuronal activity.
The mechanism of fatigue
- exhaustion or partial exhaustion of the stores of transmitter substance in the
presynaptic terminals: excitatory terminals store enough excitatory transmitter to
cause about 10,000 APs in only a few seconds to a few minutes of rapid
stimulation
- progressive inactivation of many of the postsynaptic membrane receptors
- slow development of abnormal concentrations of ions inside the postsynaptic
neuronal cell.
Some Special Characteristics of Synaptic Transmission
Effect of Acidosis or Alkalosis on Synaptic Transmission.
-most neurons are highly responsive to changes in pH of the surrounding
interstitial fluids.
-normally, alkalosis greatly increases neuronal excitability: a rise in arterial blood
pH from the 7.4 norm to 7.8 to 8.0 often causes cerebral epileptic seizures
because of increased excitability of some or all of the cerebral neurons - asking a
person who is predisposed to epileptic seizures to overbreathe  blows off carbon
dioxide and therefore elevates the pH of the blood momentarily, but even this short
time can often precipitate an epileptic attack.
- acidosis greatly depresses neuronal activity; a fall in pH from 7.4 to below 7.0
usually causes a comatose state. For instance, in very severe diabetic or uremic
acidosis, coma virtually always develops.
Some Special Characteristics of Synaptic Transmission
Effect of Hypoxia on Synaptic Transmission.
Neuronal excitability - highly dependent on an adequate supply of oxygen. Cessation
of oxygen for only a few seconds can cause complete inexcitability of some neurons
(when the brain’s blood flow is temporarily interrupted  within 3-7 sec. the person
becomes unconscious).
Effect of Drugs on Synaptic Transmission.
-caffeine, theophylline, and theobromine, which are found in coffee, tea, and
cocoa, respectively, all increase neuronal excitability, presumably by reducing the
threshold for excitation of neurons.
-strychnine is one of the best known of all agents that increase excitability of
neurons, by inhibiting the action of some normally inhibitory transmitter substances,
especially the inhibitory effect of glycine in the spinal cord  the effects of the
excitatory transmitters become overwhelming, and the neurons become so excited
that they go into rapidly repetitive discharge, resulting in severe tonic muscle
spasms.
-most anesthetics increase the neuronal membrane threshold for excitation and
thereby decrease synaptic transmission at many points in the nervous system.
Because many of the anesthetics are especially lipid soluble, it has been reasoned
that some of them might change the physical characteristics of the neuronal
membranes, making them less responsive to excitatory agents.
Synaptic Delay
(1) discharge of the transmitter substance by the presynaptic terminal,
(2) diffusion of the transmitter to the postsynaptic neuronal membrane,
(3) action of the transmitter on the membrane receptor,
(4) action of the receptor to increase the membrane permeability, and
(5) inward diffusion of sodium to raise the excitatory postsynaptic
potential to a high enough level to elicit an action potential.
The minimal period of time required for all these events to take
place, even when large numbers of excitatory synapses are
stimulated simultaneously, is about 0.5 millisec. = synaptic delay.
By measuring the minimal delay time between an input cascade of impulses
into a pool of neurons and the consequent output, one can estimate the
number of series neurons in the circuit.