Synaptic transmission

Chapter 6

pages 156 - 169

Information transmission

Action potentials (APs) initiated by depolarizing stimulus

Two general sources of depolarizing stimulus in neurons Receptor potentials from sensory transduction Information transmission between neurons

APs are intracellular events that encode information Limited to individual cells by the cell membrane

Information transmission

Transmission of information usually requires multiple cells Convergence - multiple cells with a single target Divergence - single cell with multiple targets

Need mechanism to “inform” target cells of APs Two types of mechanisms for transmitting

information encoded by APs Direct electrical coupling Release of chemical messengers

Electrical coupling

Cells are connected by ion channels that span two lipid bilayers

AP in one cell creates a voltage difference Ions flow down voltage gradient and depolarize second cell Advantages

Very rapid transmission of information

Disadvantages Does not reflect all-or-none nature of APs (any depolarization is

transmitted) Effects on target cell limited to depolarization or hyperpolarization

Electrical coupling

Electrical coupling

Used to coordinate contraction in cardiac and smooth muscle Coordinated contraction of heart to optimize blood flow Coordinated contraction of smooth muscle lining digestive

system and other organs Recently found to have important role in some

areas of the brain Synchronizes oscillatory activity in small networks of

interneurons May be important for timing or gating of information

transmission

Chemical coupling

AP can lead to release of chemical messenger Hormones Neurotransmitters

Advantages Ligand release coupled to APs Can evoke a variety of responses in target cell One way communication

Disadvantages Slower than electrical coupling

Juxtaposition of chemical release and target receptors reduces transmission delay

By far most common method of information transmission in body Neuron → neuron Neuron → muscle Neuron → gland or organ

Which of the following is an advantage of electrical coupling?

1 2 3 4 5

20% 20% 20%20%20%1. Signal initiated only in response to APs

2. Faster than chemical coupling

3. Produces a variety of postsynaptic effects

4. Maintains one way communication

5. All of the above

Synapse structure

Presynaptic – transmitting information Postsynaptic – receiving information Synaptic terminal protrudes from axon of presynaptic cell

Usually small size (100 – 500 nm across) Contains vesicles of neurotransmitter ligand Postsynaptic density on postsynaptic cell dendrite contains

neurotransmitter receptors Ionotropic (change ions) receptors are ligand-gated ion channels Metabotropic (change metabolism) receptors initiate intracellular

signaling cascades Presynaptic terminal and postsynaptic density separated by

very small (10 – 20 nm) synaptic cleft This minimizes transmission time from presynaptic → postsynaptic

The Synapse

Presynaptic release of neurotransmitter

Neurotransmitter release initiated by AP propagating into presynaptic terminal

Large transient depolarization of presynaptic terminal opens voltage-gated Ca2+ channels

Increase in intracellular free Ca2+ initiates a cascade of events that result in exocytosis of vesicles containing neurotransmitter Vesicle membranes contain specialized Ca2+ binding proteins SNARE proteins facilitate docking of vesicles on inner surface of

plasma membrane Ca2+ binding protein synaptotagmin initiates fusion of vesicle and

plasma membrane for exocytosis

Presynaptic release of neurotransmitter

Higher presynaptic [Ca2+]i increases rate of exocytosis until saturation [Ca2+]i increases with number and rate of APs traveling toward

presynaptic terminal Neurotransmitter ligand diffuses across synaptic cleft and

binds to postsynaptic receptors Ligand binding is terminated by enzymatic breakdown within

cleft or active reuptake of neurotransmitter molecules by neighboring cells

Many psychiatric and psychotropic drugs function to prevent neurotransmitter uptake or breakdown Prolongs ligand - receptor binding by maintaining ligand

concentration in synaptic cleft

How does a depolarization from a presynaptic AP lead to the release of neurotransmitter?

1 2 3 4

25% 25%25%25%1. Ca2+ influx through voltage-gated Ca2+ channels

2. K+ influx through voltage-gated K+ channels

3. Na+ influx through voltage-gated Na+ channels

4. Vesicle docking proteins are voltage-gated

Postsynaptic potentials

Neurotransmitter binding can open ligand-gated ion channel on postsynaptic density

Resulting ionic flux can be depolarizing or hyperpolarizing depending on ionic species that permeates open channels

EPSP – excitatory postsynaptic potential Depolarization due to opening of Na+ or Ca2+ permeant

ligand-gated ion channels Termed “excitatory” since Vm of postsynaptic cell is

pushed closer to AP threshold

Postsynaptic potentials

IPSP – inhibitory postsynaptic potential Hyperpolarization due to opening of K+ or Cl- permeant ligand-gated

ion channels Termed “inhibitory” since Vm of postsynaptic cell is pushed farther

from AP threshold

PSPs – general term for both EPSPs and IPSPs Characteristic time course due to diffusion, binding and

unbinding of neurotransmitter ligand Desensitization - closing of ligand-gated ion channel while

ligand is still bound to receptor Similar to inactivation of voltage-gated Na+ channel during

depolarization Requires removal of ligand before channel can open again

A neurotransmitter activates a ligand-gated K+ channel. This should produce:

1 2 3 4

25% 25%25%25%1. An EPSP

2. An IPSP

3. Both

4. Neither

Synaptic integration

In most neurons, a single EPSP will not drive postsynaptic Vm past AP threshold

Postsynaptic APs are typically evoked by simultaneous synaptic inputs from convergent sources

Temporal summation – rapid EPSPs from same presynaptic terminal Example: repetitive activation of terminal labeled “A”

Spatial summation – simultaneous EPSPs from different presynaptic terminals Example: simultaneous activation of terminals labeled “A” and “B”

IPSPs will serve to negate EPSPs or drive Vm below AP threshold

Synaptic strength

Unlike APs, PSPs are graded and can vary in amplitude and time course

Presynaptic factors affecting PSP amplitude and time course Rate of neurotransmitter synthesis Amount of neurotransmitter per vesicle Amount of Ca2+ entry per presynaptic AP Number of vesicles Up or down regulation of neurotransmitter release via intracellular signaling

molecules Synaptic cleft factors affecting PSP amplitude and time course

Cleft geometry and neurotransmitter diffusion Uptake or breakdown of neurotransmitters

Postsynaptic factors affecting PSP amplitude and time course Spatial or temporal summation of PSPs Number of neurotransmitter receptors Up or down regulation of neurotransmitter receptors via intracellular

messengers

Possible Actions of Drugs on a Synapse

Synaptic strength

Many drugs called neuromodulators act to modulate neurotransmitter release

Other neuromodulators prevent activation of neurotransmitter receptor by ligand

Many presynaptic terminals have axo-axonic synapses to modulate neurotransmitter release

Many presynaptic terminals have autoreceptors that bind to transmitters released from same terminal Serves as negative feedback to prevent excess release of neurotransmitter

Many diseases affect synaptic transmission Tetanus – bacterial toxin that destroys proteins involved in inhibitory

neurotransmitter release Most toxins from venomous species are potent antagonists of voltage-

and ligand-gated ion channels Paralyze or kill prey by preventing APs or synaptic transmission

Presynaptic (axo-axonic) synapse

A drug increases an EPSP produced by a pre-synaptic input. This drug could be acting by:

1 2 3 4

25% 25%25%25%1. Increased reuptake of the neurotransmitter

2. Increased Ca2+ influx through voltage-gated Ca2+ channel

3. Presynaptic autoreceptor that decreases vesicle docking

4. Postsynaptic GPCR that decreases response of ligand-gated ion channel

Neurotransmitters

-ergic refers to the type of neurotransmitter a neuron releases Acetylcholine (ACh) and cholinergic neurotransmission

Primary excitatory neurotransmitter in PNS Used by somatic and preganglionic autonomic neurons Degraded by enzyme acetylcholinesterase Nerve gas Sarin inhibits acetylcholinesterase

Catecholamines – derivatives of tyrosine Includes dopamine and epinephrine Broken down by monoamine oxidase (MAO) MAO inhibitors used to treat psychiatric disorders Dopamine linked to Parkinson’s disease Epinephrine (adrenaline) and norepinephrine (noradrenaline)

regulate heart rate and blood pressure

Neurotransmitters

Other biogenic amines Called biogenic amines due to synthesis from amino acid precursors Serotonin or 5-hydroxytryptophan (5-HT) associated with alertness,

appetite, emotional state Prozac blocks 5-HT uptake, LSD blocks 5-HT receptors Histamine associated with immune and injury responses Antihistamines to prevent cold symptoms and inflammation

Amino acids Major source of excitatory and inhibitory neurotransmitters in brain Glutamate receptors (GluRs) are majority of excitatory ligand-gated

ion channels in brain Glycine and GABA (-amino butyric acid) are majority of inhibitory

ligand-gated ion channels in brain Many drugs including barbiturates and benzodiazepines (Valium) act

at GABA receptors

Neurotransmitters

Neuropeptides – small polypeptides Mainly involved in pain sensation and analgesia Opiate receptors target of morphine and codeine

Other neurotransmitters ATP can act as neuromodulator Diffusable gases nitric oxide and carbon monoxide act at

intracellular receptors Not classical neurotransmitter because they don’t require

vesicles to be released Release is of nitric oxide and carbon monoxide is driven

by presynaptic production