Synapses and Synaptic Transmission Dr. Donald Allen

Learning Objectives Describe the basic features of a synapse. Describe the events that occur at a synapse from the time an action potential reaches the synapse to the time when the neurotransmitter is released. Describe the electrical changes that occur at the postsynaptic terminal. Describe the mechanism for presynaptic facilitation and presynaptic inhibition. Explain the differences between ligand-gated ion channels and G-protein mediated receptors.

Identify the major second messenger systems in the nervous system. Identify the major neurotransmitter systems in the nervous system and their major functions. Identify the primary excitatory and inhibitory neurotransmitters in the brain and spinal cord. Describe the stages that occur in the life of a neurotransmitter molecule, (including storage in vesicles, release into the synaptic cleft, binding to receptors and either degradation or reuptake by the presynaptic terminal) and identify drugs that may interfere at these stages. Describe the mechanism and role of receptor regulation Describe the pathology of Lambert-Eaton syndrome and Myasthenia Gravis.

What are synapses? What is their function?

Main Components of a Synapse Presynaptic terminal Postsynaptic terminal Synaptic cleft Vesicles Neurotransmitters

Where are Synapses located? A synapse is between the axon of the presynaptic neuron and a region of the postsynaptic cell. Where do we see synapses on the postsynaptic cell? Do synapses with different locations have different functions?

Axo- http://faculty.washington.edu/chudler/synapse.html

How Synapses Function Action potential reaches presynaptic terminal Calcium enters presynaptic terminal Voltage-gated calcium ion channels Vesicles move toward release site Presynaptic terminal releases neurotransmitter Neurotransmitter binds to postsynaptic receptors Membrane channel changes configuration and ions enter postsynaptic cell Can also activate intracellular messengers

What determines how much neurotransmitter is released?

Electrical Potentials at the Synapse Neurotransmitter binding to receptors can open ion channels At the neuromuscular junction or at axosomatic and axodendritic synapses, ion channel opening can generate a local postsynaptic potential The potentials can be depolarizing or hyperpolarizing

Postsynaptic potentials Excitatory postsynaptic potential – EPSP De- or hyper-polarization Nicotinic ACh receptor – _____________ _____________ channels Inhibitory postsynaptic potential – IPSP _____________ ion channels

Actions of EPSPs In nervous system At neuromuscular junction EPSPs can summate to generate an action potential _____________ At neuromuscular junction Each action potential in motor neuron produces a sufficient EPSP in muscle that there is muscle contraction

Actions of IPSPs IPSPs can inhibit the generation of an action potential What happens when there are both EPSPs and IPSPs at a postsynaptic neuron

Presynaptic Facilitation Where are the synapses Axo- Depolarization – Makes an action potential last ________ at the second axon presynaptic terminal The number of calcium ions that enter the presynaptic terminal is _____________

Presynaptic Facilitation The change in calcium ions causes more vesicles to release their neurotransmitter

Presynaptic Inhibition Hyperpolarization – Makes an action potential last ________ at the second axon presynaptic terminal The number of calcium ions that enter the presynaptic terminal is _____________ The change in calcium ions causes less vesicles to release their neurotransmitter

Neurotransmitters and Neuromodulators Excite or inhibit postsynaptic neuron Effect lasts less than 1/10th of a second Neuromodulator Effect G-proteins which activate second messengers Longer lasting (minutes to days)

Functional and Anatomical Organization of Neurochemical Systems Local circuits Diffuse systems Relay systems

Classification of Neurotransmitters and Neuromodulators Acetylcholine Amino acids Monoamines Peptides Other

Acetylcholine Cholinergic systems Receptors N M Amanita muscaria http://www.du.edu/~kinnamon/3640/neurotransmitters/

Acetylcholine Metabolism Acetyl-Coenzyme A and Choline Choline acetyltransferase (CAT) Acetylcholine Acetylcholinesterase (AChE) Acetate and Choline

Peripheral ACh Neuromuscular junction Autonomic nervous system Receptor: Function: Autonomic nervous system Receptors:

Central ACh Receptors Function Both nicotinic and muscarinic Autonomic regulation Selection of objects of attention

Amino Acids Main neurotransmitters of central nervous system Excitatory amino acids Aspartate Glutamate Inhibitory amino acids Glycine Gamma-aminobutyric acid (GABA)

Glutamate Principal fast neurotransmitter Functions Learning Development Neuronal death after CNS injury

Inhibitory Amino Acids

Both act to prevent excessive neural activity Glycine Inhibits postsynaptic membranes, particularly in brainstem and spinal cord GABA Major inhibitory neurotransmitter in CNS Interneurons in spinal cord Receptors: GABAA and GABAB Both act to prevent excessive neural activity Blocking the effects of these neurotransmitters can produce seizures

Monoamines Moderate sized group Cell bodies of these neurons? Norepinephrine (noradrenaline) Dopamine Serotonin Histamine Cell bodies of these neurons? Overall functions?

Catecholamines: Dopamine and Norepinephrine Phenylalanine Tyrosine Dihydroxyphenyl-alanine (l-DOPA) Dopamine

Further metabolism of catecholamines Dopamine Norepinephrine Epinephrine

Structure of some catecholamines

Dopamine Motor activity (Parkinson’s Disease) l-DOPA Cognition (Schizophrenia) Dopamine receptor blockers Motivation Addiction Cocaine Amphetamine

Norepinephrine Autonomic nervous system Attention and Vigilance Fight or fight response Panic disorder Attention and Vigilance

Serotonin AKA 5-hydroxytryptamine

Serotonin functions Regulation of blood vessels Low levels of serotonin associated with depression and suicide SSRI – selective serotonin reuptake inhibitors Fluoxetine (Prozac) Sleep

Histamine Concentrated in hypothalamus Helps regulate hormonal function

Peptides Very broad category Many different functions More modulators than neurotransmitters There are several families of peptides

Peptide release Many neurons contain both a peptide neuromodulator and a more traditional neurotransmitter With low stimulation, usually the neuron releases just the neurotransmitter With high levels of stimulation, both the peptide and the neurotransmitter are released

Endogenous opioid peptides Bind to the same receptors that opiate drugs bind to Three families Endorphins Enkephalins Dynorphins Each family comes from a different gene

In general, involved in pain inhibition Endorphins and enkephalins involved in ‘runner’s high’ Also important in regulation of hormonal systems

Substance P P is for pain Substance P acts as a neurotransmitter in some of the neurons in the sensory pathways that relay pain sensation

Other peptides ACTH (pituitary) Vasopressin (pituitary) Neurotensin Cholecystokinin Somatostatin (hypothalamus)

Miscellaneous Neurotransmitters Nitrous oxide Neuromodulator Regulates vascular systems Cell death of neurons Changes in postsynaptic neuron in response to repeated stimuli Carbon monoxide Short-lasting, rapid effects Affects neurotransmitter release

Receptors Most neurotransmitters and neuromodulators act by binding to specific proteins on the postsynaptic membrane termed receptors Substances which bind to receptors are called ligands Most receptors named after the ligand that binds to them Some important exceptions

Types of Receptors Ligand-gated ion channels G-protein mediated receptors

Ligand-gated ion channels Receptor and ion channel are the same complex Actions usually rapid and brief Mechanism Ligand binds to receptor Ion channel opens Ions travel through channel Local membrane depolarization or hyperpolarization

Nicotinic Acetylcholine Receptor Located at neuromuscular junction Best studied receptor Made up of 5 subunits

Nicotinic AChR Two molecules of ACh bind to the receptor Ion channel opens Permeable to both Na+ and K+ Overall effect is depolarization More Na+ enters than K+ leaves the muscle fiber Channel open for only a few milliseconds

Action at the receptor ends when: Neurotransmitter diffuses away from the synaptic cleft Neurotransmitter is broken down into an inactive form Acetylcholinesterase (ACh) Monoamine oxidase (monoamines) Peptidases (peptide neuromodulators) Neurotransmitter is taken up into the presynaptic terminal

G-protein mediated receptors AKA: 7-transmembrane receptor Picture next slide Effects slower and longer lasting Open/close ion channel Activate/inhibit enzymes Regulate calcium levels in cell Activate/inactivate genes

Beta-2 adrenergic receptor

Mechanism of Action Can be stimulatory, inhibitory or modulatory Involve activation/inhibition of second messenger systems Note that this can give us amplification of the ligand. One ligand-activated receptor can produce multiple 2nd messengers. If the 2nd messengers activate enzymes, we have a further magnification of the response

Second messengers Cyclic AMP (cAMP) Modulates ion channels (pain sensation in PNS) Activates cAMP dependent proteins/enzymes Arachidonic acid – derived from lipids Produces prostaglandins – aspirin blocks PG synthesis regulate vasodilation Enhances inflammation Inositol triphosphate Regulates Calcium ion stores

G-protein action cAMP as 2nd Messenger

G-protein action Phosphoinositol as 2nd Messenger

Types of Receptors Acetylcholine Aminoacid Norepinephrine Dopamine Serotonin Opioid peptide

Acetylcholine Receptors Nicotinic – ligand-gated ion channel Neuromuscular junction Autonomic ganglia Some parts of CNS Functions Memory and learning Alzheimer’s disease Neuronal development

Muscarinic Acetylcholine Receptors G-protein linked receptors Autonomic targets – heart Selected areas of brain Autonomic function – Parasympathetic Slow heart

Glutamate Receptors Both ion channels and G-protein linked Ion Channels – named for drugs that bind AMPA – fast acting Kainate – fast acting NMDA – slow opening and closing of ion channels G-protein – metabotropic receptors

NMDA receptors Function Normal neurotransmission Long-term changes in the CNS Long-term potentiation (next section) Learning and memory

NMDA receptors and pathology Neuronal cell death Injury to part of the brain can produce cell death in surrounding regions Overactivity may cause epileptic seizures Phencylclidine (PCP, angel dust) acts on NMDA receptors Other pathologies Acute stroke, chronic pain, Parkinson’s disease, schizophrenia

GABA receptors GABA-A receptors Chloride ion-channel linked Effect on cell membrane? Barbiturates bind Sedation Decrease anxiety (anxiolytic) Anticonvulsants for treating seizures

Baclofen – muscle relaxant All GABA receptors tend to be inhibitory GABA-B receptors G-protein mediated Linked to ion channels through 2nd messengers Baclofen – muscle relaxant All GABA receptors tend to be inhibitory

Dopamine Receptors Dopaminergic receptors 5 types – D1, D2, D3, D4, D5 Main types D1, also D3, D5 D2, also D4 D1 and D2 can have the opposite effects

Norepinephrine receptors Alpha-receptors (alpha-1 and alpha-2) Beta-receptors (beta-1 and beta-2) Beta-1 Heart: increase force and rate of contraction Beta-blockers Beta-2 Lungs: bronchodilation Inhalers for asthma

Serotonin receptors 5-HT receptors Cognition Sleep Multiple types Cognition Sleep Perception (including pain) Motor activity Mood

Opioid peptide receptors Several types Mu Delta Kappa Primary action is inhibition of slow pain information Location: hypothalamus, spinal cord, and periaqueductal gray

How can we change synaptic transmission? Drugs can interfere at many different stages Synthesis of neurotransmitter Packaging in vesicles Regulating calcium ions in presynaptic terminal Release of neurotransmitter from vesicles Binding of neurotransmitter to receptors Degradation of neurotransmitter Re-uptake of neurotransmitter

Synthesis of Neurotransmitter l-DOPA

Packaging in vesicles Reserpine

Calcium Ion regulation Lambert-Eaton syndrome

Neurotransmitter release Botulinum toxin poisoning Blocks release of ACh at the neuromuscular junction Used to treat (short-term) spasticity Used for cosmetic reasons

Receptor binding Agonists Antagonists Myasthenia gravis

Neurotransmitter Degradation Monoamine oxidase inhibitors (MAO-I) Acetylcholinesterase inhibitors

Neurotransmitter Reuptake Tricyclic antidepressants Inhibit monoamine reuptake Tend to act at cholinergic receptors also Selective serotonin reuptake inhibitors Prozac (serotonin)

Lambert-Eaton Syndrome Mostly seen in patients with cancer, usually small cell carcinoma of the lung Antibodies are produced against voltage-gated calcium channel of the neuromuscular junction Antibodies block calcium entry into presynaptic terminal What affect will this have on ACh release and muscle strength?

Myasthenia gravis Antibodies to the nicotinic acetylcholine receptor Antibody blocks the effect of ACh on the muscle Increasing weakness seen with repeated use of a muscle Initial sign in about 50% of patients Weakness opening eyelids or moving eyes. Why?

Other muscles commonly affected Facial muscles Muscles for swallowing Proximal limb muscles Respiratory muscles Demographics of onset Women: 20-30 Men: 60-70

Treatment Acetylcholinesterase inhibitors Removal of thymus gland Immunosuppressive drugs Plasmapheresis: removes antibodies

Questions before Chapter 4