L5-6: Synaptic Transmission I-II

Question 1

Two types of synapses (contacts)

Answer 1

1. ) Electrical

2. ) Chemical (neuron-neuron, neuron-muscle)

Question 2

What is a gap junction? How are signals passed between cells at gap junction? What are connexins? Which synapses are they associated with? Function?

Answer 2

• Gap junctions = membrane protein composed of connexin subunits to form a connexon (6x - semi-channel), of which two make contact between two cell membranes. These serve as channels that are permeable to ions and small molecules serving as communication between electrical activity
• Gap junctions associated with electrical synpases
• Function: synchronize electric activity among populations of cells

Question 3

Properties of electrical synapse

Answer 3

• Bidirectional
• Fast
• Low selectivity to small ions and molecules (only large size is selected against)

Question 4

Mechanism by which APs cause neurotransmitter release.

Answer 4

1. NT in vesicles and vesicles are docked with SNARE proteins
2. AP invades pre-synaptic terminal and depolarizes membrane
3. Voltage gated Ca channels located at/near docking complexes open and Ca flows into the cell along electrochemical gradient in a localized manner.
4. With higher Ca levels, synaptic vesicles fuse with presynaptic membrane and release NT via exocytosis
5. Release via full fusion or via kiss/run discharge

Question 5

Describe recovery phase after NT release from pre-synaptic terminal

Answer 5

1. ) presynaptic terminal repolarizes as K leaves through VG K channels
2. ) VG Ca channels close, Ca unable to flow into terminal
3. ) Free ionized CA is removed from cytoplasm via diffusion, calcium binding proteins and transported to internal Ca stores such as ER or pumped outside of cell via Na/Ca ATPase pumps
4. ) Vesicles are endocytosed via clathrin-mediated endocytosis and recycled

Question 6

What is the general role of SNARE proteins?

Answer 6

• Collection of transmembrane proteins located at vesicles and pre-synaptic PM that form a complex for vesicle docking and fusion
• Calcium is necessary to mediate this process

Question 7

What is synaptic delay? What are the causes of it? Types of receptors associated with long synaptic delay times? Is synaptic delay shorter at chemical or electrical synapses?

Answer 7

• Defined at time interval bw when AP arrives at pre-synaptic terminal and when membrane potential change begins in post-synaptic cell
• Causes: synaptic vesicle fusion event, diffusion of NT across synaptic cleft, activation of postsynaptic channels
• Types of receptors with long delay times = metabotropic receptors, which many times involve production of protein rather than a membrane potential change
• Synaptic delay is shorter at electrical synapses (ie. These are faster at less than 0.1 msec), chemical synapses have greater delay (1-2 msec) and are slower

Question 8

Mechanism of removing NT from synaptic cleft

Answer 8

1. ) diffusion away from site
2. ) enzymatic degradation – eg. ACh esterase
3. ) NT re-uptake into pre-synaptic terminal or adjacent astroglia

Question 9

What is the chemical basis of cocaine addiction?

Answer 9

• Cocaine binds to DA (or NE/5-HT) transporters locaed at pre-synaptic terminals resulting in increase in synaptic DA level. DA is reward signal NT.

Question 10

What are synaptic sites of antidepressant actions?

Answer 10

• MAOIs: monoamine oxidase inhibitors prevent degradation of 5-HT
• TCAs (tricyclic antidepressants) and SSRIs (selective serotonin reuptake inhibitors) block uptake at synaptic sites
• 5-HT deficiency underlies depressive symptoms, therefore these drugs aim to increase/return 5-HT levels to normal

Question 11

Describe synaptic transmission at NMJ. Include role of ACh esterase

Answer 11

• Previously described events occur at pre-synaptic terminal causing release of ACh
• ACh diffuses across cleft and binds ACh receptors at end-plate
• ACh receptor (ionotrophic) is ligand-gated ion channel permeable to both Na/K but with greater permeability to Na. Activation of receptor allows Na in, K out, net depolarization, which is called an end-plate potential (EPP – like EPSP specific to NMJ), a local potential
• Depolarization if large enough spreads to part of sarcolemma containing VG Na channels and causes AP
• EPP terminated by hydrolysis of ACh by AChesterase
• Re-uptake of choline into motor neuron – NB as choline not synthesized

Question 12

What is an EPSP? Describe mechanism that causes depolarization. Discuss which ion permeabilities are affected.

Answer 12

• Excitatory post-synaptic potential: inputs from pre-synaptic terminal that depolarize the postsynaptic cell bringing it closer to threshold and closer to firing AP
  Mechanism:
  1.) Excitatory NT (eg. glutamate) binds excitatory type receptor on post-synaptic membrane, which are ionotropic and permeable to both Na and K, but more to Na than K
  2.) Binding of glutamate to receptor leads to net influx of Na down its electrochemical gradient, leading to depolarization of membrane – this is the EPSP, a local potential
  3.) Small depolarization increases probability that post-synaptic cell will initiate AP, but on EPSP is usually not enough. EPSPs must spread via passive conduction to area of membrane that can initiate AP – called initial segment

Question 13

True/False. EPSP involves VG sodium channels.

Answer 13

• False

- Only ligand-gated ion channel

Question 14

What is an IPSP? Describe mechanism that causes hyperpolarization and / or inhibits postsynaptic cell. Discuss which ion permeabilities are affected.

Answer 14

• Inhibitory post-synaptic potential: inputs from pre-synaptic terminal that hyperpolarize the post-synaptic cell bringing it further away from threshold and firing an AP
  Mechanism:
  1.) Inhibitory NT (eg. GABA) binds inhibitory type receptor on post-synaptic membrane, which are ionotropic and permeable to Cl.
  2.) Binding of GABA to receptor causes influx of Cl into cell, hyperpolarizing the membrane away from threshold – this is the IPSP, a local potential.
  • Can also have inhibitory effects via metabotropic receptors that increase K permeability – leads to K efflux and hyperpolarization

Question 15

Define temporal summation and spatial summation

Answer 15

• Temporal summation: when single pre-synaptic terminal has two or more APs in rapid succession and potentials sum up in post-synaptic cell
• Spatial summation: two or more separate post-synaptic potentials reach initial segment simultaneously stimulating AP

Question 16

Usual effect of glycine, GABA and glutamate – inhibitory or excitatory?

Answer 16

• Glycine: inhibitory via opening of chloride channel
• GABA: inhibitory via opening of chloride channel (GABA-A – ionotropic receptor) and opening K channels or suppression of Ca channels (GABA-B – metabotropic receptor)
• Glutamate: excitatory via channel permeable to Na/K/Ca – more to Na

Question 17

Two major classes of post-synaptic receptors. Describe differences

Answer 17

1. ) Ionotropic receptors (aka ligand-gated ion channel receptor): ligand (NT) binds and forms channel, directly changes channel’s permeability, responsible for fast chemical synaptic transmission
2. ) Metabotropic receptors (G-protein coupled): receptor coupled with G-protein, ligand binding initiates G-protein signaling and elicits different physiologic effects incl. changing conductance of channel by directly opening or closing ion channel, slower acting on membrane potential

Question 18

How can metabotropic receptors cause excitatory effects? Inhibitory effects?

Answer 18

• Excitatory: decreasing conduction through chloride or K channels
• Inhibitory: increasing conduction through chloride or K channels
  • these are both slow changes

Question 19

Describe briefly how the following diseases/toxins affect synaptic transmission: a.) Myasthenia gravis, b.) Eaton-Lambert syndrome, c.) botulinum toxin, d.) tetanospasmin/toxin e.) alpha-bungarotoxin. Is problem pre- or post-synaptic? Which are autoimmune?

Answer 19

a. ) Myasthenia gravis: autoimmune dz with autobodies against nACH-R causing reduction in number of nicotinic-ACh receptors at post-synaptic NMJ leading to small EPPs possibilities therefore muscle weakness and paralysis
b. ) Eaton-Lambert syndrome: autoimmune attack on VG calcium channels in terminals of somatic motor nerves leading to less ACh release. Occurs in pts with certain types of CA esp. small cell carcinoma of lungs (and in some breast CAs).
c. ) Botulinum toxin: cleave regions on synaptic vesicle or pre-synaptic PM proteins (SNAREs) at motor neurons interfering with release of NT – leads to flaccid paralysis
d. ) Tetanospasmin toxin: also cleave SNARE proteins, but at interneurons leading to disinhibition and hyperexcitation of motor neuron leading to tetanic/spasmic contraction and tetanus
e. ) Alpha-bungarotoxin: irreversibly blocks nicotinic-ACh-receptor leading to paralysis and respiratory failure

Question 20

Treatment of myasthenia gravis

Answer 20

• Neostigmine is a reversible AChE inhibitors – indirectly enhances function of existing AChR by increasing EC ACh level
• Edrophonium is a reversible, but short acting AChE inhibitor used in diagnosis

Question 21

What are active zones and how are they different between synapses in CNS and in NMJ?

Answer 21

• Active zone are regions of the pre-synaptic membrane that is specialized for vesicular release of NT – there are numerous in NMJ synapses, but single active zone at CNS synapses

Question 22

Types of receptors seen at NMJ on muscle? What is it permeable to?

Answer 22

• nicotinic-ACh-receptors – permeable to both Na/K, but more to Na
• No inhibitory receptors

Question 23

Effect of tubocurarine

Answer 23

• older n-ACh-R blocker used to paralyze pts during surgery, it is the active form of curare

Question 24

Effect of sarin

Answer 24

• aka “nerve gas” is irreversibly binds AChE

Question 25

Two types of ACh receptors

Answer 25

1. ) Nicotinic – fast, ionotropic

2. ) Muscarinic – slower, metabotropic via G-protein linked

Question 26

Examples of amine NTs. What does serotonin and histamine bind?

Answer 26

• Catecholamines: DA, NE, Epi
• Serotonin (aka 5-HT) – binds several types of 5-HT receptors
• Histamine – binds several histamine receptors (H1-4)

Question 27

Examples of catecholamines. What are they derived from? What receptors do they bind?

Answer 27

• Dopamine (DA), norepinephrine (NE) and epinephrine (Epi)
• Derived from tyrosine
• DA binds dopamine receptors
• NE and Epi bind adrenergic and noradrenergic receptors

Question 28

Classes of adrenergic receptors

Answer 28

1. ) Alpha – greater affinity for NE

2. ) Beta – greater affinity for Epi

Question 29

Examples of AA NTs. What are the effects: inhibitory or excitatory? What receptors does each bind?

Answer 29

1. ) GABA: inhibitory – binds to receptors belonging to two classes, GABA-A and GABA-B
2. ) Glycine: inhibitory, binds to glycine receptors
3. ) Glutamate and aspartate: excitatory, binds to 3 different classes of receptors: AMPA, kainate and NMDA

Question 30

What are purinergic NTs? What receptors do they bind? Function?

Answer 30

• Adenosine (part of ATP) is not stored in vesicles and is a neuromodulator that binds to A-type purinergic receptors (aka adenosine receptors) and is a CNS depressant. Caffeine, theophylline (in tea) and theobromine (in chocolate) are adenosine receptor blockers
• ATP that is co-released with other NT binds to P-type purinergic receptors. Function??

Question 31

What are neuroactive peptides? Compare and contrast how these are synthesized vs how small-molecule NTs are synthesized.

Answer 31

• These are molecules that act as hormones, NTs or neuromodulates including opioid peptides (endorphins, enkephalins and dynorphins), vasopressin, oxytocin etc.
• Synthesized in the nucleus and require precursor molecules and enzymes to produce final product that are transported to nerve terminals. Small molecule NTs are often synthesized in nerve terminal. Large peptides are also packaged into larger synaptic vesicles and are not released via same docking complex and small molecule NTs.

Question 32

Example(s) of gaseous NTs

Answer 32

• NO

Question 33

Which NT is created by enzymatic degradation of membrane lipids? What do these bind?

Answer 33

• Endocannabinoids: anandamide and 2-arachindonylglycerol (2-AG)
• Bind endocannibinoid receptors CB1 and CB2, which binds THC from cannabis