Transcript Neuroscience in PT: Introduction and Review

PTP 512
Neuroscience in Physical Therapy
Introduction
Neurotransmitters
Min H. Huang, PT, PhD, NCS
Concepts you should already
know before this lecture
• Cell membrane ion channels
• Resting membrane potential
• Local potential
– Temporal summation
– Spatial summation
• Action potential
• EPSP
• IPSP
Types of Synapses in the CNS
HETEROSYNAPTIC PLASTICITY
Presynaptic Inhibition and
Facilitation
• Axoaxonic synapses mediate presynaptic
inhibition and facilitation, e.g. present in
the spinal cord to regulate the propagation
of information to the brain.
• Interneurons regulate the ability of the
presynaptic neurons to release
neurotransmitters by changing the amount
of Ca++ influx to the presynaptic neurons.
Presynaptic Facilitation
 1 release
1 Interneuron
2 Presynaptic neuron
transmitters
 Transmitters bind to 3 Postsynaptic neuron
receptors on 2
 This causes 2 to
release more
transmitters into the
synaptic cleft
between 2 & 3 when
an action potential
arrives
Presynaptic Inhibition
 1 release
1 Interneuron
transmitters
2 Presynaptic neuron
 Transmitters bind to 3 Postsynaptic neuron
receptors on 2
 This causes neuron 2
to release less
transmitters into the
synaptic cleft when
an action potential
arrives
Syn – together
Haptein – to clapse
SYNAPSE
Electrical vs. Chemical Synapse
http://www.ncbi.nlm.nih.gov/books/NBK11164/
Type
Electrical
Chemical
Length of
synaptic cleft
Cytoplasmic
continuity
Structure
3.5 nm
20-40 nm
Yes
No
Gap junction
Agents of
transmission
Synaptic delay
Direction of
transmission
Ion current
(electrical)
Virtually absent
Bidirectional
Presynaptic
vesicles
Postsynaptic
receptors
Neurotransmitters
(chemical)
> 1-5 ms
Unidirectional
Chemical Synapse
Dobrunz,
2002
Synaptic Communication
Lundy’s CD - Synapse
Synaptic Communication
• Total # of action potentials reaching the
presynaptic terminal directly influences the
amount of neurotransmitter released
• ↑excitatory stimuli to the presynaptic
neuron cause increased # action potentials
reaching the presynaptic terminal
• ↑duration of excitatory stimuli to the
presynaptic neuron cause a longer series of
action potentials reaching the presynaptic
terminal
NEUROTRANSMITTERS AND
NEUROMODULATORS
What is a Neurotransmitter?
• It is synthesized in the neuron
• It is present in the presynaptic terminal
• It is released in amounts sufficient to exert
an action on the postsynaptic neuron or
effector organ
• It is removed from the synaptic cleft by a
specific mechanism
– Synaptic vesicle cycling
http://neuroscience.uth.tmc.edu/s1/cha
pter05.html
Schwartz, 2005
What is a Neurotransmitter?
• When administered “exogenously” (e.g.
drugs) in reasonable concentration, it
mimics the action of the endogenously
released neurotransmitter exactly. It
activates the same ion channels or second
messenger system in the postsynaptic cell.
Some define neurotransmitters to include
neuromodulators that act away from the
synaptic cleft (Blumefeld, 2010).
Schwartz, 2005
What is a Neuromodulator?
•
•
•
•
Act at a distance away from the synapse
Modulate activity of many neurons
Released into extracellular fluid
The same chemical substance can act either
as a neurotransmitter or neuromodulator
• Effects last minutes to days
• Neurotransmitters and
neuromodulators can be
released simultaneously
Functions of Neurotransmitters
• Mediate communication between neurons
or the end-organs through fast excitatory
(EPSP) or inhibitory (IPSI) postsynaptic
potentials (<1 ms)
– Directly opening ligand-gated ion
channels on postsynaptic membrane
• Slow-acting neuromodulation, occurring
over 100ms to minutes
– Indirect opening ion channels or
activation the cellular signaling cascades
Neurotransmitter Receptors
• Receptors are often named according to the
neurotransmitters to which they bind, e.g.
GABAA, GABAB, 5-HT receptors
• The same neurotransmitter may bind to
several types of receptors, e.g. Serotonin
• The effect of neurotransmitters on a
postsynaptic neuron is determined by the
type of receptors present on its membrane,
e.g. Ach, Norepinephrine
Signal Transmission Mechanisms:
Direct Activation of Ion Channels
Lundy’s CD
Neurotransmitters bind
to receptors that are
part of the ligand-gated
ion channels and
directly open the ion
channels.
Signal Transmission Mechanisms:
Indirect Activation of Ion Channels
Neurotransmitters bind
to receptors that are
separate from the ion
channels, and indirectly
open the ion channels
by activating the Gprotein. This process
involves changes in the
metabolism of the cell.
Lundy’s CD
Signal Transmission Mechanisms:
Activating Intracellular Signaling
Activation of the Gprotein secondmessenger system can
trigger the intracellular
signaling cascade. This
process has long lasting
effects on regulating
genes expression and
neuronal growth.
Byrne, 1997
Termination of Synaptic Transmission
• Removing neurotransmitters
– Diffusion: remove a fraction only
– Enzymatic degradation: e.g.
acetylcholinesterase
– Reuptake: most common, e.g. serotonin
• Desensitizing receptors by
– Receptor internalization: folding the
postsynaptic membrane containing the
receptors into the cell
– Receptor inactivation
Common Neurotransmitters and
Neuromodulators
• Amino Acid
— GABA
— Glutamate (Glu)
— Glycine (Gly)
• Cholinergic
— Acetycholine
(ACh)
• Amine
— Dopamine (DA)
— Serotonin (5-HT)
— Norepinephrine
(NE)
• Peptide
— Substance P
— Endorphins
Amino Acid: GABA
• Fast-acting MAJOR inhibitory
neurotransmitter found in the entire CNS,
e.g. inhibitory interneurons in spinal cord
• Prevents excessive neural activity
Barbiturates mimics the action of GABA and
are used for sedation, as anticonvulsants.
Baclofen, a muscle relaxant to control
muscle spasticity, increases presynaptic
release of GABA
Amino Acid: Glutamate (Glu)
• Fast-acting MAJOR excitatory
neurotransmitter found in the entire CNS
• Involved in learning and memory
• Glutamate is present in a wide variety of
foods, e.g. MSG
Overactivity of glutamate may cause
seizures
Excitotoxicity: Excessive glutamate may
produce neuronal damage or death, e.g. TBI
or CVA (X1000 higher than normal)
Glutamate Receptors
• AMPA: ligand gated receptor
• NMDA: ligand- and voltage-gated receptor
– Postsynaptic neuron must depolarize
when the Glu binds to the NMDA
receptor in order to open the gate
– Prolonged opening of ion channels
resulting in long-term potentiation (LTP)
• Metabotropic glutamate receptor: indirect
activation by G-protein pathway
NMDA
Receptor
Channel is
permeable to
Na+, Ca++, K+,
opens and closes
very slowly.
LTP plays an
important role in
neuroplasticity.
Byrne, 1997
Acetylcholine (ACh)
• MAJOR neurotransmitters in PNS, ANS
– Fast-acting effect: act at neuromuscular
junction, e.g. Nicotinic receptors
– Slow-acting effect: regulate HR, ANS
function, e.g. Muscarinic receptors
• Primary as a neuromodulator in CNS
– Controls locomotion, arousal
– Facilitate attention, memory, learning
ACh Receptors
Nicotinic Receptor
Muscarinic Receptor
Byrne, 1997
Nicotinic
Muscarinic
Bind nicotine
Bind muscarine
Linked to ion channels Liked to 2nd messenger
system through G protein
Fast and brief
Slow and prolonged
response
response
Located at
Found on myocardial
neuromuscular
muscle, certain smooth
junctions, autonomic muscle, in some CNS
ganglia, and some CNS regions
Mediate excitation
Mediate inhibition and
excitation
Cholinergic
Projection
Systems
Blumefeld, 2010
Acetylcholine
Applying electrical stimulation to
pontomesencephalic region of the
brainstem elicits coordinated locomotor
movements.
Drugs that block the cholinergic
transmission in the brain causes delirium
and memory deficits.
Degeneration of cholinergic neurons in the
basal forebrain may be associated with
memory decline in Alzheimer’s disease
Myasthenia Gravis (MG)
• ACh receptors on muscle membranes are
destroyed . Weakness becomes more severe
with repetitive use of a muscle.
• Rx: Anticholinesterase inhibits the
cholinesterase from breaking down ACh.
Myasthenia Gravis (MG)
Reduced EMG amplitudes
over repetitive muscle
contractions.
Case: a 12-year-old girl with
cerebral paly
She walks on her toes and exhibits a scissor
gait, with legs strongly adducted with each
step. Standard physical therapy has not
resulted in any significant improvements.
Her physicians want to inject a small amount
of Botulinum toxin (Botox) into the
gastrocnemius and adductor magnus muscles
of both legs to reduce involuntary muscle
activity and improve gait.
Questions
• By what mechanism could the injection of
Botox reduce involuntary muscle activity?
• At the neuromuscular junction, ACh acts via
a ligand-gated receptor. Is the action of ACh
on the nicotinic, ligand-gated receptor the
same as its action on the muscarinic, Gprotein-mediated receptor?
The effect of Botox lasts about 12 weeks.
Too much ACh leads to spasm or tremor
Too little ACh leads to paralysis or delirium
Amines: Dopamine (DA)
• Produced in substantia nigra of basal
ganglia and ventral tegmentum
• Primarily an inhibitory effect in CNS
• All DA receptors are 2nd messenger systems
to suppress the activity of Ca++ channels.
• Affects motor activity, motivation/reward
behavior, and cognition
Dopamine Projecting System
BG
Movement
Limbic
Reward
Addiction
Prefrontal
Working Memory
Attention
Neurologic Conditions Associated
with Dopamine (DA)
Parkinson’s Disease Case: ↓DA in basal
ganglia
Depression/Cognitive: ↓DA in forebrain
Drug addiction: cocaine and amphetamines
interfere with DA reuptake into the
presynaptic neurons, allowing DA to
activate receptors repetitively
Schizophrenia: too much DA
Amines: Serotonin (5-HT)
• Produced in raphe nuclei and GI tract
• Serotonin regulates sleep-wake cycle,
cognition, perception of pain, breathing,
temperature, movements, and mood.
• Serotonin is associated with depression,
anxiety, obsessive-compulsive disorder,
aggressive behavior, certain eating
disorders (release serotonin ↓appetite)
• Serotonergic neurons ↓firing during sleep
Amines: Serotonin (5-HT)
Serotonin is “happiness hormone”.
Serotonin ↓perception of pain. Low levels
of serotonin are associated with
depression.
Prozac (antidepressant) is a selective
inhibitor of serotonin reuptake (so
serotonin stays in the synaptic cleft longer
to bind with receptors)
SIDS may be associated with defected
serotonergic neurons.
Serotonin
Projecting
System
Noradrenergic
Projecting
Systems
Blumefeld, 2010
Norepinephrine (NE)
• Regulate functions of ANS, thalamus, and
hypothalamus
• Modulate attention, sleep-wake cycle
– Noradrenergic neurons ↓firing in sleep
– Attention-deficit disorders if often
treated with medications that enhance
NE transmission
• ↑level of NE is associated with vigilance,
↑alertness, and “fight-or-flight” response
Norepinephrine (NE)
• Noradrenergic neurons involve in
sympathetic functions such as blood
pressure control
Similar to Serotonin, NE also ↓perception
of pain in the CNS, and plays a role in many
psychiatric syndrome
– ↓NE can cause depression
– ↑NE can cause anxiety (panic attack)
Serotonin
Projection
System
Noradrenergic
Projecting
Systems
Blumefeld, 2010
Histamine
• Found mainly in the hypothalamus.
• Found mostly outside the nervous system in
mast cells that mediate immune responses
and allergic reactions.
• Role of histamine in the brain
– Maintain the alert state
– Excitatory effects on thalamus
Antihistamine medications can cause
drowsiness by blocking CNS histamine
receptors
Peptides: Substance P
• Released from the terminals of some
sensory nerve fibers
• Neurotransmitter function in the
nociceptive pathway
– stimulates free nerve endings at the site
of injury and transmit pain signals from
the periphery to the CNS
• Neuromodulator function in the chronic
pain syndrome
– increase pain perception
Peripheral sensitization
following cell damage.
Pain signals cause the
free nerve endings to
release substance P.
5-HT outside the nervous
system stimulates the
nociceptive free nerve
endings.
SP-substance P
H-histamine
5HT-serotonin
Hauser, 2010
Peptides: Endogenous Opioids
(endorphin, enkephalin, dynorphin)
• Body’s natural pain
killers
• Inhibit CNS neurons
involved in the
perception of pain
• Exercise increases
endogenous opioids
Nitric Oxide (NO)
• An free radical, highly reactive, diffusible
gas molecule with neuromodulator effects
• NO is important in the regulation of
cerebral blood flow, neurotransmission,
long-term potentiation, excitotoxicity (i.e.
neuronal death)
• NO cause blood vessels to dilate
• NO in excess is toxic to cells
Review
• What would be the functional implication
of presynaptic facilitation and inhibition?
• Describe the structure of a chemical
synapse and the events of signal
transmission at the synapse.
• Compare and contrast neurotransmitters
versus neuromodulators.
• Discuss the functions of neurotransmitters
and the associated clinical implications.