PTP 512Neuroscience in Physical Therapy

IntroductionNeurotransmitters

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 Facilitation1 Interneuron2 Presynaptic neuron3 Postsynaptic neuron

1 release transmitters

Transmitters bind to 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 Interneuron2 Presynaptic neuron3 Postsynaptic neuron

1 release transmitters

Transmitters bind to receptors on 2

This causes neuron 2 to release less transmitters into the synaptic cleft when an action potential arrives

SYNAPSE

Syn – togetherHaptein – to clapse

http://www.ncbi.nlm.nih.gov/books/NBK11164/

Electrical vs. Chemical Synapse

Type Electrical ChemicalLength of synaptic cleft

3.5 nm 20-40 nm

Cytoplasmic continuity

Yes No

Structure Gap junction Presynaptic vesiclesPostsynaptic receptors

Agents of transmission

Ion current (electrical)

Neurotransmitters (chemical)

Synaptic delay Virtually absent > 1-5 msDirection of transmission

Bidirectional Unidirectional

Dobrunz, 2002

Chemical Synapse

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/chapter05.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

Neurotransmitters bind to receptors that are part of the ligand-gated ion channels and directly open the ion channels.

Lundy’s CD

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 G-protein. This process involves changes in the metabolism of the cell.

Lundy’s CD

Signal Transmission Mechanisms: Activating Intracellular Signaling

Activation of the G-protein second-messenger 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 activityBarbiturates 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. MSGOveractivity of glutamate may cause seizuresExcitotoxicity: 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 MuscarinicBind nicotine Bind muscarineLinked to ion channels Liked to 2nd messenger

system through G proteinFast and brief response

Slow and prolonged response

Located at neuromuscular junctions, autonomic ganglia, and some CNS

Found on myocardial muscle, certain smooth muscle, in some CNS regions

Mediate excitation Mediate inhibition and excitation

Cholinergic Projection

Systems

Blumefeld, 2010

AcetylcholineApplying 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, G-protein-mediated receptor?

The effect of Botox lasts about 12 weeks.Too much ACh leads to spasm or tremorToo 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 Limbic Prefrontal Movement Reward Working Memory Addiction Attention

Neurologic Conditions Associated with Dopamine (DA)

Parkinson’s Disease Case: ↓DA in basal ganglia

Depression/Cognitive: ↓DA in forebrainDrug 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 PH-histamine5HT-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.