Transcript Neurophysiology Neurotransmitter and Nervous System

Neurophysiology, Neurotransmitters
and the Nervous System
The Neuron
The nervous system is
made of nerve cells or
neurons and glial cells.
Glial cells are not
excitable and provide
metabolic and physical
support for the neurons.
90% of the cells are glial
cells. Neurons are
excitable and control
behavior
Neuron
Resting potential
Resting potential
There is a potential
difference between the
inside and outside of as
membrane. The inside
is about -70 mv
relative to the outside.
Resting Potential
The resting potential is
caused by an uneven
distribution of ions
(electrically charged
molecules) of potassium
(K+) and sodium (Na+)
and chloride (Cl-).
This is caused by Na+/K+
ion pumps that move 3
Na+ ions out of the cell for
every 2 K+ ions it moves
in.
Therefore there are more
+ions outside the cell than
inside and the inside is
negatively charged with
respect to the outside
Ion pump
Resting potential
An ion channel is a combination
of large protein molecules that
cross the membrane and allow
specific ions to pass through at a
specific rate,
These allow enough leakage of
ions to mostly neutralize the
effect of the ion pump, but
Ion channels
Resting potential
Forces



maintaining the resting potential
Diffusion pressure – molecules want to move
from areas of high concentration to areas of low
concentration.
Electrostatic charge – ions with like charge are
repelled and ions with a different charge are
attracted.
Operation of ion pumps and ion channels.
Action potential
Anything
that alters the functioning of the ion
channels can change the resting potential.
If
changes cause the resting potential to be
reduced, this is called depolarization.
If
the change causes an increase in the resting
potential, this is caused hyperpolarization.
Action Potential
We
can insert an electrode across a
membrane and cause depolarization, i.e.,
we can depolarize the cell.

If we reduce the resting potential past a
threshold, the resting potential breaks
down.
Action potential
Voltage
gated ion channels open and let Na+ into the cell.
They are driven into the cell because of diffusion gradient
and electrostatic charge.
This
causes the resting potential to reverse, i.e., the inside
the cell becomes positive.
Now
the Na+ ion channels close and the K+ channels open
and the K+ ions are driven out of the cell because of their
concentration gradient and electrostatic charge.
Finally
the K+ channels close and the ion pumps kick in
and the resting potential returns to normal.
Action potential
All or None Law
 Action
potentials when they occur are
always the same.
 Once the process is initiated, it must run its
course and nothing can stop it or change it
Transmission of action potentials along
a membrane
 When
an action potential occurs at one
place on the membrane of an axon, the
surrounding membrane is depolarized past
threshold causing an action potential. This
depolarizes the neighboring membrane,
etc.
 Action potentials sweep across a
membrane as fast as 100m/sec
Transmission of action potentials along
a membrane
Postsynaptic potentials
 The
membranes of dendrites and cell
bodies do not have action potentials.
Instead, any depolarizing stimulus causes
a post synaptic potential (PSP) which
spreads out across the membrane. The
depolarization is weaker the further it gets
from the stimulus. When the stimulus is
turned off, the PSP disappears.
Postsynaptic potentials
 Postsynaptic
potentials can either be
excitatory (depolarization) or inhibitory.
 Excitatory and inhibitory potentials can
summate both in time (temporal
summation) and across the membrane
(spatial summation) .
 The net effect of summation is reflected at
the axon hillock where action potentials are
generated.
The synapse
 Normally,
cell bodies are stimulated by
either by
stimuli in the environment, e.g. sensory cells like
the rods and cones in the eye, or
 Connections from other nerve cells, i.e.,
synapses

The Synapse
The Synapse
Synapse
Any neuron can have thousands of synapses on it
Synapse
 When
an action potential arrives at the terminal
bouton, it causes Ca++ channels to open.
 This causes the vesicles to move to the membrane
and release a chemical called a neurotransmitter
to be released into the synaptic cleft.
 The neurotransmitter diffuses across the cleft and
activates receptors on the postsynaptic membrane
which cause changes on the resting potential by
altering the functioning of ion channels.
Proteins
 Ion
pumps, ion channels, etc., are large
molecules of protein.
 Proteins are long strings of amino acids that can
fold into many three dimensional shapes. The
same protein can have different configurations,
i.e., they can change shape.
 Receptors are protein molecules that change
shape (are activated) by neurotransmitter
molecules with a particular shape.
Receptors

Receptor sites can be
part of an ion channel
and when the receptor
site is occupied by a
neurotransmitter, the
ion channel opens
Post synaptic potential
 The
change in the resting potential caused by the
activation of a receptor site is called the post
synaptic potential (PSP).
 IPSP – when the change causes
hyperpolarization or makes the cell harder to fire,
this is called an inhibitory post synaptic potential.
 EPSP – when the change causes depolarization,
this is called an excitatory post synaptic potential.
Post synaptic potential
The excitation and inhibition caused by all
the active synapses on the dendrites and
cell body are summed and the net effect is
reflected in the rate at which the axon hillock
generates action potentials
Summation
Terminating synaptic action
 Once
the neurotransmitter is released into
the cleft, there must be a means by which
its activity is terminated. This can be
accomplished two ways


The neurotransmitter can be destroyed by an
enzyme in the cleft
The neurotransmitter can be reabsorbed back
into the bouton (reuptake).
Second messenger
The neurotransmitter causes the release of a
molecule inside the cell which activates an ion
channel and causes it to open
Second messenger cascade
Second messenger cascade
Second
messenger molecules can activate a
kinase which lasts for minutes and hours.
Kinases
can activate transcription factors
(CREB and c-fos) which alter the expression of
genes.
Genes
carry the codes for the creation of proteins
including ion channels and receptor sites and this
can cause permanent changes in synaptic
function.
autoreceptors
 The
membrane of the presynaptic cell has
many receptor sites which detect the
neurotransmitter. This is a feedback
system which regulated the amount of
neurotransmitter released into the cleft
Other signaling between neurons
Neuromodulators are chemicals that can alter the effect of a
neurotransmitter.
Sometimes the postsynaptic membrane releases molecules
that affect the presynaptic membrane.
DSE- depolarization-induced suppression of
excitation
DSI – depolarization-induced suppression of inhibition.
Axo-axonal synapses: axons may also have synapses
Neurotransmitters
Acetylcholine (Ach)
Biogenic amines (monoamines)
catecholamines:
Norepinephrine (NE)
Dopamine (DA)
Epinephrine (E) (adrenaline)
indoleamine
Serotonin (5-HT, 5-hydroxytryptamine)
Amino acids:
GABA
Glycine
Glutamate
Proline
Peptides
Substance P
Somatostatin
Vasopressin
Growth hormone
Prolactin
Insulin
Opiate-like transmitters
Enkephalins
Endorphins
carbon monoxide
nitric oxide
Many hormones are neurotransmitters. Both have the
same function: chemical signalling over distances.
Neurohormones
Substances that act at neuron receptor
sites, but are not specific to an individual
synapse.
May be released far from the synapse.
Act as a neuromodulator (modify the
activity of a neurotransmitter)
Dale’s Law
A single neuron always produces the same
transmitter at every one of its synapses.
It is now known that the law is not always right.
Drugs mostly act on the nervous system by interacting
with neurotransmission,
They may:
act on receptor sites and cause the same effect as a
transmitter: agonism
block a receptor site: antagonism
decreasing activity of enzymes that destroy a
transmitter
block reuptake mechanisms
blocking ion channels
altering release of transmitter
altering the action of neurohormones
Synapses that use NE are nor adrenergic (remember,
adrenaline is another word for epinephrine)
DA are dopaminergic
5-HT are serotonergic
ACh are cholinergic
etc
Acetylcholine:
Broken down by AchE (acetylcholinesterase)
Receptors: nicotinic and muscarinic
Stimulated Blocked
nicotinicnicotine
curare
Function
Voluntary muscle control
(neuromuscular junctions)
muscarinic
muscarine
botox and nerve gasses
atropine
Involuntary muscle control
Biogenic amines
Serotonin, Dopamine Norepinephrine and
Epinephrine
Broken down by MAO and COMT
Reabsorbed by transporter mechanisms
Influenced by amphetamines and cocaine and SSRIs and
SNRIs
E and NE receptor sites alpha (α)and Beta (β) with
subtypes 1 and 2
DA has 6 receptor subtypes D1 and D2....D6 with sub sub
types a b c, etc
Serotonin has 4 main receptor subtypes with sub sub
types a b c etc.
GABA
 Universally
inhibitory transmitter
 Opens a Chloride ion channel which stabilizes the
membrane and makes it harder to depolarize
 Drugs like benzodiazepines enhance the ability of GABA
to open the ion channel.
 There are two types of GABA receptors; GABAA and
GABAB.
 There are many different subtypes of GABAA receptors
which control different functions.
 GABAB receptors are less common and use a second
messenger
GABA
Glutamate
excitatory transmitter
NMDA receptor open ion channel and lets +ions
into the cell
the channels can be blocked by alcohol, solvents
and some hallucinogens
Peptides
opioid type peptides
enkephalins (5 amino acids)
endorphines (16 to 30 amino acids)
Receptor subtypes mu, kappa and delta
The Nervous System
Central Nervous System (CNS)
brain and spinal cord
Peripheral Nervous system (PNS)
everything else
somatic NS
conscious senses and voluntary muscles
transmitter is Ach and uses nicotinic
receptors
autonomic NS
unconscious senses and involuntary
muscles
transmitter is Ach with muscarinic
receptors.
Autonomic NS
sympathetic and parasympathetic divisions
Parasympathetic
always active,
controls daily vegetative functions
Ach major transmitter
some drugs have “anticholinergic” side effects,
e.g dry mouth and blurry vision
Sympathetic
active at times of fear and anger
fight - flight response
epinephrine (E) major transmitter
CNS
spinal cord
Brain
100 billion neurons. each has 100 synapses on
other neurons and receives 10,000 synapses from
other neurons
Spinal cord
Brain
Medulla:
Autonomic control centre:
Respiratory centre controls breathing
Vomiting centre
Cardiac functions
Very sensitive to “depressant” drugs like alcohol,
opioids and barbiturates
Brain damage caused by drug overdose is a result of
lack of oxygen
RAS and Raphé System
RAS - arousal
- many interconnected centres
- diffuse projection to cortex and higher centres
Raphé System
- many independent centres
- serotonin
- medial forebrain bundle projects forward
- sleep
- mood
Locus Coeruleus
mood: fear, panic, anger
primarily NE, (50 to 75% NE neurons in the brain)
stimulated by monoamines
inhibited by GABA
active during panic attack
Cerebellum:
Coordination of motor control
Receives input from the motor areas of the cortex and the
muscles and coordinates smooth muscle movement.
Coordinates eye movements.
Basal Ganglia:
Input side:
striatum – caudate nucleus and putamen
- input from thalamus and cortex
Output side:
globus palladus - output side with feedback to thalamus
“Motor loop”
coordination of motor control
- DA input from substantia nigra
- DA receptors
- DA deficiency - Parkinsons Disease
- extrapyramidal motor system
Periaquiductal gray:
pain control - mu receptors and morphine-like
transmitters
punishment system
Limbic system:
hypothalamus - eating and drinking control
medial forebrain bundle
--- reinforcement (pleasure?) centres
mesolimbic system (DA)
ventral tegmental area (VTA, mu receptors)
nucleus accumbens
hippocampus - learning and memory
amygdala and septum - serotonergic input from the
Raphé system
Aggression and emotion
Inhibited by GABA
Cortex
Cortex
sensory input areas
motor control output areas
language
memory and thinking
glutamate - excitatory
transmitter
GABA - inhibitory transmitter
Frontal and prefrontal cortex
Frontal and prefrontal cortex: monitors relationship
between cues and reinforces (outcomes of behavior),
inhibition of behavior and the expression of emotion.
Orbitofrontal cortex: learning and behavior control
Prefrontal cortex: working memory, attention, decision
making, reasoning, planning and judgment.
Dorsolateral prefrontal cortex: maintenance of attention
and manipulation
Anderior cingulate cortex: attention, response selection,
response suppression, drug seeking and craving.
Development
Formation of neurons
Migration
Attachment and axon projection
Growth cone
Development and teratology
Extension of axons is controlled by trophic factors, chemical signals that guide
it to its target.
These signals can be easily disrupted by drugs and cause incorrect wiring of
the CNS
Eg: fetal; alcohol syndrome – only 4 layers rather than the normal 6 in the
cortex.
Teratology: disruption of normal anatomical development, e.g thalidomide
Functional teratology: a disruption of normal behavioral development.