Objectives
•
•
•
•
•
•
Synapses
• a nerve signal AP travels to the end of the axon
– triggers the release of a neurotransmitter
– stimulates a new wave of electrical activity in the next cell
across the synapse
Synapses
Neurotransmitters
Temporal & Spatial Summation
EPSP & IPSP
Coding
Memory
• synapse between two neurons
– presynaptic neuron
– postsynaptic neuron
• neuron can have an enormous number of synapses
– spinal motor neuron covered by about 10,000 synaptic
knobs from other neurons!!!!
• 8000 ending on its dendrites
• 2000 ending on its soma
12-1
• in cerebellum of brain, one neuron can have as many as
100,000 synapses
12-2
Synaptic Relationships Between Neurons
Structure of a Chemical Synapse
Soma
Synapse
Axon
• synaptic knob of presynaptic neuron contains synaptic
vesicles containing neurotransmitter
Presynaptic
neuron
Direction of
signal
transmission
– many on release plasma membrane waiting to be released
– others located further away from membrane
Postsynaptic
neuron
(a)
• postsynaptic neuron membrane contains proteins that
function as receptors and ligand-regulated ion gates
Axodendritic synapse
Axosomatic
synapse
Axoaxonic synapse
(b)
12-3
Structure of a Chemical Synapse
Neurotransmitters and Related Messengers
Microtubules
of cytoskeleton
Axon of presynaptic neuron
Mitochondria
Postsynaptic neuron
Synaptic knob
Synaptic vesicles
containing neurotransmitter
Synaptic cleft
Neurotransmitter
receptor
Postsynaptic neuron
Neurotransmitter
release
• synaptic vesicles with neurotransmitter
• receptors and ligand-regulated ion channels
12-4
12-5
• more than 100 neurotransmitters!!
• 4 major categories according to chemical composition
1. acetylcholine
• in a class by itself
2. amino acid neurotransmitters
• include glycine, glutamate, aspartate, and -aminobutyric
acid (GABA)
3. monoamines
• synthesized from amino acids after removal of –COOH group
– retaining the –NH2 (amino) group
• major monoamines are:
– epinephrine, norepinephrine, dopamine (catecholamines)
– histamine and serotonin
4. Neuropeptides
• Chains of amino acids
12-6
1
Categories of Neurotransmitters
Acetylcholine
H3C
Monoamines
CH3
O
N+ CH2 CH2 O C CH3
CH3
OH
CH CH2 NH CH2
Amino acids
HO
HO
C CH2 CH2 CH2 NH2
O
HO
C CH2
OH
CH CH2 NH2
Norepinephrine
HO
HO
NH2
Glycine
O
OH
Glu
Glu Phe
N
Phe Gly
Leu Met
Substance P
ß-endorphin
Ser
Serotonin
Glu
N
O
C
CH2 CH2 NH2
N
Aspartic acid
C CH CH2 CH2
HO
NH2
Dopamine
HO
C CH CH2 C
OH
NH2
O
Pro
Phe
Asp Tyr Met Gly Trp Met Asp
Met
Phe
Ser Thr
SO4
Gly
Cholecystokinin
Glu
Gly
Tyr
Lys
CH2 CH2 NH2
HO
Tyr
Arg Pro Lys
GABA
O
HO
Gly Gly
Enkephalin
Epinephrine
HO
O
Met Phe
Catecholamines
HO
Neurotransmitters at a Synapse
Neuropeptides
CH2 CH2 NH2
Thr
Histamine
Glutamic acid
Ala
Pro
IIe
IIe
Val
Thr Leu
• released in response to stimulation (An AP!)
• bind to specific receptors on postsynaptic cell
Lys Asn Ala Tyr
Asn
Lys
Leu
• synthesized by the presynaptic neuron
Phe
Lys
Lys
Gly
Glu
• alter the physiology of postsynaptic cell
– (i.e. cause local potential)
12-7
12-8
Synaptic Transmission
Effects of Neurotransmitters
• neurotransmitters are diverse in their action
• a given neurotransmitter does not have same effect
everywhere in the body
• multiple receptor types exist for a particular
neurotransmitter
– 14 receptor types for serotonin
– some excitatory (EPSP)
– some inhibitory (IPSP)
– effect depends on what kind of receptor the postsynaptic cell
has
• some receptors are ligand-regulated ion gates
• some receptors act through second-messenger systems
• three kinds of synapses with different modes of action
• receptor governs the effect the neurotransmitter has
on the target cell
– excitatory cholinergic synapse
– inhibitory GABA-ergic synapse
– excitatory adrenergic synapse
• synaptic delay – arrival of signal at axon terminal to AP
12-9
12-10
Excitatory Cholinergic Synapse
•Involve Acetylcholine
ACh excites some
postsynaptic cells
(skeletal muscle)
•Na+ enters the cell it
spreads out along the
inside of the plasma
membrane and
depolarizes it
producing a local
potential
•if it is strong enough
and persistent
enough
it opens voltageregulated ion gates
in the trigger zone
• AP!!!
Presynaptic neuron
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Presynaptic neuron
3
Ca2+
1
2
ACh
Na+
4
K+
5
Postsynaptic neuron
12-11
2
Excitatory Adrenergic Synapse
Excitatory Adrenergic Synapse
• Adrenergic synapse employs the neurotransmitter
norepinephrine (NE) (aka noradrenaline) (
• NE and other monoamines, and neuropeptides act through
second messenger systems such as cyclic AMP (cAMP)
• The receptor is not an ion gate, but a transmembrane
protein associated with a G protein
Secondary Messenger
System
Presynaptic neuron
has advantage of enzyme
amplification
single molecule of NE can
produce vast numbers of
product molecules in the
cell
Postsynaptic neuron
Neurotransmitter
receptor
Norepinephrine
Adenylate cyclase
G protein
–
– –
+
+ +
1
2
3
ATP
cAMP
Ligandregulated
gates
opened
4
Enzyme activation
6
Multiple
possible
effects
5
Na+
Postsynaptic
potential
7
12-13
Metabolic
changes
Genetic transcription
Enzyme synthesis
Cessation of Synapse
Inhibitory GABA-ergic Synapse
• Usually Neurotransmitter is its receptor for brief time – replaced by
another
1.
stop adding neurotransmitter get rid of that which is already there
– stop signals in the presynaptic nerve fiber
2. Getting rid of neurotransmitter
• diffusion
– into nearby ECF
– astrocytes in CNS absorb it and return it to neurons
• GABA-ergic synapse employs -aminobutyric acid as its
neurotransmitter
• nerve signal triggers release of GABA into synaptic cleft
• GABA receptors are chloride channels (Cl- anions)
• Reuptake and breakdown
– synaptic knob reabsorbs amino acids and monoamines by
endocytosis
– break neurotransmitters down with enzymes
• Cl- enters cell and makes the inside more negative than the
resting membrane
• Membrane becomes Hyperpolarized
– Postsynaptic neuron is inhibited - less likely to fire
12-15
• Degradation in the synaptic cleft
– Enzymes
e.g., acetylcholinesterase in synaptic cleft degrades into
acetate and cholin
12-16
Neural Integration
Neuromodulators
• hormones, neuropeptides, and other messengers that modify
synaptic transmission
– may stimulate installation of more receptors in postsynaptic membrane
– may alter rate of neurotransmitter synthesis, release, reuptake, or
breakdown
• enkephalins – a neuromodulator family
– small peptides that inhibit spinal interneurons from transmitting pain
signals to the brain
• nitric oxide (NO) – simpler neuromodulator
– a lightweight gas release by the postsynaptic neurons in some areas of
brain concerned with learning and memory
– diffuses into presynaptic neuron
– stimulates release of more neurotransmitter
– neuron’s way of telling the another to ‘give me more’
12-17
• synaptic delay slows transmission of nerve signals
• more synapses in pathway, longer it takes information to
get from its origin to its destination
– synapses are not due to some limitation resulting from nerve fiber
length
– gap junctions allow some cells to communicate more rapidly than
chemical synapses
• then why do we have synapses?
– the more synapses a neuron has, the greater its informationprocessing capabilities.
• neural integration = ability of neurons to process
information, store and recall it, and make decisions
12-18
3
Postsynaptic Potentials - EPSP
Postsynaptic Potentials - IPSP
• inhibitory postsynaptic potentials (IPSP)
– any voltage change away from threshold that makes a neuron
less likely to fire
• neurotransmitter hyperpolarizes postsynaptic cell making
it more negative than the RMP - less likely to fire
• produced by neurotransmitters that open ligand-regulated
chloride gates
Excitatory postsynaptic potentials (EPSP) any voltage
change increasing the chance of a neuron firing.
• usually results from Na+ flowing into the cell
• typical neuron has a resting membrane potential of ~70 mV and threshold of about -55 mV
– glycine and GABA produce IPSPs and are inhibitory
– acetylcholine (ACh) and norepinephrine are excitatory to
some cells and inhibitory to others
• depends on the type of receptors on the target cell
• ACh excites skeletal muscle, but inhibits cardiac muscle
due to the different type of receptors
Any change getting membrane closer to -55 is EPSP
12-19
Postsynaptic Potentials
12-20
Summation
0
• A neuron can receive input from thousands of other neurons
–20
mV
• Some synapses produce EPSPs while others produce IPSPs
–40
Threshold
–60
Repolarization
–80
(a)
• Post-synaptic neuron’s response depends on whether net input is
excitatory or inhibitory
Resting membrane
potential
EPSP
• Summation – process of adding up postsynaptic potentials and
responding to their net effect
– occurs in the trigger zone
Depolarization
Stimulus
Time
0
mV
–20
• The balance between EPSPs and IPSPs enables the nervous
system to make decisions
–40
Threshold
–60
IPSP
Resting membrane
potential
–80
Hyperpolarization
(b)
Stimulus
12-21
12-22
Time
Temporal and Spatial Summation
Summation of EPSPs
+40
+20
3 Postsynaptic
neuron fires
0
1 Intense stimulation
by one presynaptic
neuron
mV
Action potential
2 EPSPs spread
from one synapse
to trigger zone
–20
(a) Temporal summation
–40
–60
–80
Threshold
EPSPs
Resting
membrane
potential
Stimuli
3 Postsynaptic
neuron fires
Time
12-23
2 EPSPs spread from
several synapses
1 Simultaneous stimulation to trigger zone
by several presynaptic
neurons
12-24
(b) Spatial summation
4
Facilitation, and Inhibition
Neural Coding
• Neurons often work in groups to modify each other’s action
• CNS recieves a coded message
• facilitation – one neuron enhances the effect of another one
– combined effort of several neurons - summation of EPSP!!!!!!
• presynaptic inhibition – process in which one presynaptic neuron
suppresses another one
– reduces or halts unwanted synaptic transmission
– neuron I releases inhibitory GABA
1. Where is the message coming from?
– labeled line code – each nerve fiber to brain leads from a specific
fiber
– Brain recognizes where its from and what stimulus type
Signal in presynaptic neuron
Signal in presynaptic neuron
2. What type of stimulus is it? (What type neuron sent info)
Signal in inhibitory neuron
3. How strong is the message? (intensity)
No activity in inhibitory
neuron
- Frequency of APs
I
I
• CNS can judge stimulus strength from the firing frequency of afferent neurons
Neurotransmitter
No neurotransmitter
release here
IPSP
Inhibition of presynaptic
neuron
S
Neurotransmitter
Excitation of postsynaptic
neuron
EPSP
S
No neurotransmitter
release here
R
(a)
No response in postsynaptic
neuron
R
12-26
(b)
12-25
Neural Coding
Neural Pools and Circuits
•
neurons functioning in large groups, each of which consists of millions of
interneurons concerned with a particular body function
– control rhythm of breathing
– moving limbs rhythmically when walking
•
information arrives at a neural pool through one or more input neurons
– branch repeatedly and synapse with numerous interneurons in the pool
Discharge zone – input synapses many times w postsyn. (temporal
summation)
Facilitated zone – require facilitation – more pre- neurons required to fire
Action potentials
2g
•
•
5g
One or more
Input neurons
10 g
20 g
Figure 12.28
Time
12-27
Types of Neural Circuits
Diverging
Discharge zone
Facilitated zone
12-28
Memory and Synaptic Plasticity
• Physical basis of memory is a pathway through the brain
called a memory trace or engram
– along this pathway, new synapses were created or
existing synapses modified to make transmission
easier
– synaptic plasticity – ability of synapses to change
– synaptic potentiation - process of making
transmission easier
Converging
Input
Facilitated zone
Output
Output
Input
Reverberating
Parallel after-discharge
Figure 12.30
Input
Input
Output
• kinds of memory
– immediate, short- and long-term memory
– correlate with different modes of synaptic potentiation
Output
12-29
12-30
5
Immediate Memory
Short-Term or Working Memory
• short-term memory - lasts from a few seconds to several hours
– quickly forgotten if distracted
– calling a phone number we just looked up
– reverberating circuits
• immediate memory – ability to hold something in
your thoughts for just a few seconds
– essential for reading ability
• feel for the flow of events (sense of the present)
• Synaptic facilitation causes memory to last longer
– tetanic stimulation –
• rapid arrival of repetitive signals at knob
• causes Ca2+ accumulation in knob
• Release of more and more neurotransmitter
• postsynaptic cell more likely to fire
• our memory of what just happened “echoes” in our
minds for a few seconds
– post-tetanic potentiation - to jog a memory
• Ca2+ level in synaptic knob stays highly elevated
• AP causes massive amount of neurotransmitter release
12-31
12-32
Molecular Changes & Long-Term Memory
Long-Term Memory
• long-term potentiation
• Involves NMDA receptors and Mg+2
• types of long-term memory
– declarative - retention of events that you can put into words
– procedural - retention of motor skills
– NMDA receptors on dendrites usually blocked by Mg +2 ions
– when bind glutamate and receive stimuli, they repel Mg +2
channel opens
– Ca+2 enters dendrite – Ca+2 acts as second messenger
• more synaptic knob receptors are produced
• synthesizes proteins involved in synapse remodeling
• releases nitric oxide that triggers more neurotransmitter
release at presynaptic neuron
• We think some LTM involves physical remodeling of synapses
– new branching of axons or dendrites
• long-term potentiation
– changes in receptors and other features increases
transmission across “experienced” synapses
– effect is longer-lasting
12-33
12-34
Alzheimer Disease
Long-Term Potentiation (LTP)
•
•
Increased Ca+ ion channel
openings i.e., neurotransmitter
released
•
deficiencies of acetylcholine (ACh) and nerve growth factor (NGF)
•
diagnosis confirmed at autopsy
– atrophy of gyri (folds) in cerebral cortex
– neurofibrillary tangles and senile plaques
– formation of beta-amyloid protein from breakdown product of
plasma membranes
genetics implicated
(Glutamate receptor)
•
Increases
EPSP
Increased Ca+ causes
Protein synthesis for
Pre-synaptic proteins (dendritic spines)
•
(calmodulin-dependent
Protein kinase II)
100,000 deaths/year
– 11% of population over 65; 47% by age 85
memory loss for recent events, moody, combative, lose ability to talk,
walk, and eat
treatment - halt beta-amyloid production
– Give NGF or cholinesterase inhibitors !
12-36
8-38
6