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Neurobiology > Exam II > Flashcards

Exam II Flashcards

1
Q

2 types of synaptic transmission

A

Electrical

Chemical

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2
Q

Compare/contrast the 2 types of synaptic transmission

A

Electrical

  • distinct minority
  • faster (no delay)
  • simpler
  • physically connected
  • maintained through gap junctions (connexons)
  • direct + passive flow of current
  • EPSP and IPSP

Chemical

  • majority
  • slower (slight delay)
  • more complex
  • mediated through NTs
  • imp: so many molecules, lots of room for things to go wrong (many neurological disorders)
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3
Q

Plasticity

A

Synaptic transmission is plastic – can be increased/decreased, allows us to memorize/learn

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4
Q

Gap junction

A

Specialized intercellular contacts formed by connexon channels that directly connect the cytoplasm of 2 cells

  • 1.5-2 nm diam (5-6x wider)
    The close connection of 2 adjacent membranes

Most of the time open, only close under certain conditions

Connected via connexon channels
  Connexons made of 6 connexin subunits
  1 connexon = hemichannel 
  2 connexons = form channel
Connexons connect 2 cells and allow direct passive current to flow
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5
Q

Connexons

A 
Connected VIA connexon channels
  Connexons made of 6 connexin subunits
  1 connexon = hemichannel 
  2 connexons = form channel
Connexons connect 2 cells and allow direct passive current to flow

Pore of connexon = 1 nm (much larger)

Connexons are highly conserved in extracellular short groups (bc that’s where they link)
Highly variable in cytoplasmic regions (bc different ones are regulated in different ways

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6
Q

Electrical coupling

A

Direct passage of signal from one neuron to the next

Allows for synchronized firing

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7
Q

Directionality of electrical transmission

A

Bidirectional – meaning that current can flow in either direction depending on which member of the coupled pair is invaded by an AP

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8
Q

What is the molecular basis for electrical transmission?

A

Gap junctions between 2 electrical cells

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9
Q

What can go through gap junctions

A

All physiologically important molecules
(Ca2+, Mg2+, Na+, K+, Cl-, bicarbonate, phosphate)

And small metabolic/signaling molecules
(AAs, glucose, ATP and 2nd messengers (i.e., cAMP, cGMP, IP3)

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10
Q

How can we quickly and easily determine whether cells are connected through gap junctions?

A

Dye-coupling experiment

You COULD stick in electrode and see if electrically coupled…but TEDIOUS

EASIER WAY: dye-coupling
Insert fluorescent dye into one cell, small enough to diffuse in 10-20 mins

GFP too big (protein), only small peptides can fit through

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11
Q

How are gap junctions closed?

A

Closed by intracellular ↑ in Ca2+ or lower pH (more H)

The junctions will be closed if exposed to acidic conditions (lower pH, more H added) or high levels of calcium

The gap junction closure by calcium ions and protons is a self-saving mechanism of the cell to protect/seal normal cells from injured or dying cells near by

Increase in Ca2+ and acidity (lower pH, higher [proton]) occurs when cells are damaged

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12
Q

Key properties of electrical synapses

A
  • rapid signalling
  • reliable
  • synchronous activity
  • direct transfer of key small molecules
  • more gap junctions present during neural dev (help them find common pways)
  • more common in NS of invertebrates

RRSDDI

RRISDD

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13
Q

Importance of electrical coupling shown through…

A

The heart ! - best example of the importance of electrical coupling

  • Highly synchronized
  • ♡beat triggered by spontaneous pacemaking in the node – travels through fibres
    For the ♡ to pump so rapidly and synchronously, you need gap junctions to allow for direct passage of current
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14
Q

Key properties of chemical transmission

A
  • Much more abundant
  • Much more versatile – fast, slow (direct, indirect);
    excitatory, inhibitory; short-term and long-term
    regulation; etc.
  • No direct flow of current between the cells
  • No direct physical connection between the cells
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15
Q

Otto Lewi experiment

A

Existence of NTs –

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16
Q

Synaptic cleft length

A

50-60 nm wide

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17
Q

Chemical synaptic transmission steps

A
  1. NTs synthesized and packed into vesicles
  2. AP invades presynaptic terminal
  3. Depolarization causes Ca2+ channels to open
  4. Influx of Ca2+ into cell
  5. Ca2+ causes vesicles to fuse with pre-membrane
  6. NTs released via exocytosis into synaptic cleft
  7. NT binds to Rs on postsynaptic membrane
  8. Channels open/close - thus changing ion flow across membrane
  9. The resulting NT-induced current flow alters membrane potential and post-synaptic cell conductance (⇅probability of cell firing)
Synthesis
AP
DC - depol/Ca channels
Influx of Ca
Fusion
Exocytosis
Receptor binding
Channels open/close

S A Dc I F E R - C

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18
Q

How do NTs affect current?

A

The resulting NT-induced current flow alters membrane potential and post-synaptic cell conductance (⇅probability of cell firing)

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19
Q

Fast synapse steps vs. slow chemical synapses steps

A

FAST - ionotropic

  1. Opening of iontropic R
  2. Generates postsynaptic current (ions flowing in/out)
  3. EPSP or IPSP
  4. ⇅ of AP firing

SLOW - metabotropic

  1. Activation of metabotropic R (usally GCPR)
  2. G protein activated
  3. 2nd messenger activated (Ca2+, cAMP)
  4. Protein kinase activated
  5. Regulation of ion channels
  6. ⇅ of AP firing
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20
Q

NMJ ballpark #s

A

7,000 ACh molecules/vessel

Synaptic cleft = 50-60 nm wide

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21
Q

Active zone

A

Regions where vesicles fuse

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22
Q

Why is the NMJ the best studied chemical synapse?

A

Simple, large, and peripherally located

great for studying chemical transmission

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23
Q

NMJ chemical transmission steps

A
  1. AP propagates to nerve terminals
  2. Voltage-gated Ca2+ channels open, increasing Ca2+ in terminal
  3. Exocytosis of ACh
  4. ACh diffuses across the synaptic cleft
  5. Binds to postsynaptic nicotinic ACh receptors (nAChRs)
  6. Na/K flow generate EPC that produces EPP
  7. If the EPP is above the action potential threshold, one or more APs will be fired in the muscle fibers
  8. Acetylcholinesterase (AChE) degrades the ACh and terminates signaling

*6. Na+ and K+ ions flow through nAChR channels, generating an inward end-plate current (EPC) into the postsynaptic cell and producing an end-plate potential (EPP)

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24
Q

How is a current defined

A

By the flow of positive ions

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25
Q

Basic metabolism of ACh in NMJ

A
  1. ACh is made up of choline and acetylCoA
  2. In synaptic cleft, ACh is rapidly broken down by AChE
  3. Choline is transported back into presyn terminal (via Na+/choline cotransporter)
    - AChE limits amount of tiem ACh is in synapse
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26
Q

ACh R and enzyme blockers

A

n ACh R:

  • nicotinic
  • blocked by curare, βbungarotoxin

AChE
- blocked by insecticides, nerve gas, neostigmine, physostigmine
==> ALLOWS ACh to remain longer in the cleft, enhanced effect of synaptic transmission at NMJ

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27
Q

Why were Katz recordings were done in partially curarized NMJ?

A

Curare will block ACh receptors, keeping EPP subthreshold

So that way electrode is not kicked out/dislodged

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28
Q

EPP experiment results

A
  • Fast rise to the peak in ~2-3 ms
  • Amp is largest near the endplates and decrease with distance – it’s a graded potential and propagates passively
  • EPP is produced by a brief surge of current at the endplate
  • EPP triggers APs when it’s large enough to reach the firing threshold
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29
Q

Katz

A

synaptic transmission pioneer

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30
Q

What produces EPP?

A

EPC - inward current that produces EPP

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31
Q

When you superimposed EPC and EPP, what do you find?

What contributes to the rise/fall of each?

A

EPC produces EPP
- this is why current rises faster than voltage

Voltage decays more slowly than EPC
- due to large capacitance of muscle membrane that slows down voltage

What causes the EPC current to decay?

  • Desensitization of ACh Rs
    1. Mean open time of nACh Rs
    2. AChE (hydrolrzes ACh in cleft, which will stop current)
    3. Diffusion of ACh (~10-15ms)
32
Q

How to test effect of AChE?

A

Use AChE inhibitor (ex: neostigmine)
Stimulate axon – EPC response will decay much more slowly

Since it still does decay, implies that other molecules are involved

33
Q

EPC

A

the macroscopic current resulting from the summed opening of many ion channels in the NMJ

Bc the EPC is normally inward, it causes the postsynaptic membrane to depolarize

34
Q

Conductance underlying EPC

A

Return to

35
Q

Structure of nAChR channel

A

Pentamer
With pore in middle (nonselective, bigger than Na/K)

Each subunit has 4 transmembrane domains

36
Q

What happens at NMJ?

How to measure what happens?

A
  1. Use voltage clamp to find reversal potential of NT R channel
    => Then can infer what ions can go through
  2. Use ion substitution to confirm
  3. Patch clamp
  4. Can do single-channel recording
37
Q

Experimentation - ion identification

A

Return to

38
Q

Why is transmission in CNS much harder to study?

A

Many inputs (100s/1000s), EPSP+IPSP, many NT types, Ionic and metabo Rs, small presyn terminals(hard to record), tiny postsyn responses (0.2-0.4 mV PSP), spatial+temporal integration

 Hundreds to thousands of inputs
 Excitatory and inhibitory inputs
 Many different types of neurotransmitters
 Different types of receptors – ionotropic vs. metabotropic
 Small presynaptic terminals – hard to record
 Tiny postsynaptic responses – 0.2-0.4 mV PSP
 Extensive spatial and temporal integration

39
Q

Excitatory v. inhibitory synapse

features

A

EPSP:

  • occurs in dendritic spines
  • large (1-2 μm^2) terminal
  • NTs: Glutamate, ACh, 5-HT, ATP
  • functional effect: more APs

IPSP:

  • occurs in soma
  • small (less than 1 μm^2) terminal
  • NTs: GABA, glycine
  • functional effect: less APs
40
Q

Synapse markers

A

PSD-95: abundantly expressed in postsynaptic density

Synapsin: presynaptic marker

41
Q

Where are excitatory synapses typically found in the CNS?

A

Dendritic spines

42
Q

GABA

A

Inhib NT

43
Q

Glycine

A

Inhib NT

44
Q

Glutamate

A

Excit NT

45
Q

ACh

A

Excit NT

46
Q

Ionotropic glutamate Rs

A

NMDA Rs
AMPA Rs
Kainate Rs

Both glutamate-gated cation channels allow Na/K passage, always produce EPSP

Most central excitatory synapses express both

47
Q

How to determine role of glutamate Rs given that nearly all have both NMDA and AMPA Rs?

A

Selective antagonist blockage…

=> NMDA currents slower + last longer
=> AMPA Rs = largest amp, therefore known as primary mediators for excitatory transmission

48
Q

AMPA R experimentation

A
  1. Express AMPA Rs (on xenoput oocytes) without dealing with other channels
  2. Do voltage clamp, then apply current
  3. Add glutamate on cell and record inward current
  4. Current will rise + decay quickly, then desensitize

If you add CAQX (AMPA antagonist), you mainly conduct inward Na+ current

Mainly conducts inward Na+ under resting conditions

49
Q

CNQX

A

Competitive AMPA/kainate R antagonist

50
Q

NMDA R experimentation

A
  1. Express NMDA Rs
  2. Clamp at -70
  3. Apply glutamate
    - We do not see response
    - Could be that rev. potential is -70…so we clamp at a different level
  4. Clamp to very low potential
    ….still no response…we only start seeing current when become less negative
    current rev. potential = 0

Researchers found that the current-voltage relationship is caused by Mg2+

– The lack of current at negative voltages is due to Mg2+ channel blockage, voltage-dependent

WHY MG2+ DIP???

51
Q

NMDA R properties

A

Common: nonselective cation channel, permeable to Na/L

Unique:

  • Permeable to Ca2+
  • Votage-dependent block by extracellular Mg2+
  • Requires glycine as a cofactor
  • Slow opening and desensitization
  • Blocked by AP5
52
Q

AP5

A

Competitive NMDA R antagonist

53
Q

How does the Mg2+ block work?

A

(voltage-dependent)

AA lining of NMDA pore = negative
Mg2+ (being pos) gets sucked into pore
The more negative the voltage, the stronger the pull on Mg2+ to block

When voltage is less negative, the pull becomes less strong –> bigger and bigger current due to less+less negative block

Degradation eventually occurs due to the driving force - as membrane potential approaches reversal potential

54
Q

How would you prove that large response due to both Rs, and how to dissect each?

A

Synapse b/w Ca3 axon and Ca1 dendrites (glutamatergic)
- stick electrode in Ca1 cell body

Apply blockers to see which Rs involved

  • Apply AP5 (NMDA R antagonist)
  • Apply CNQX (AMPA R antagonist)

If you use both antags, no response
If you use AMPA antag (CNQX), you get no response
If you use NMDA antag (AP5), you get lessened response

55
Q

Conduction effects at different stimulation

A

At strong stimulation, Mg2+ block is relieved

At low stimulation, Mg2+ exerts its effects – ∴ small current bc only one R conducting

56
Q

NMDA R channel structure

A

Most of channel is outside in extracellular domain

Contains glutamate, glycine, etc. binding sites

57
Q

Fast inhibitory synaptic transmission experimentation

A

First Stimulate neuron
Produces hyperpolarization, 15-20 ms lasting

  1. Do voltage clamp
    Outward current produces hyp.
    Find rev. potential -75 mV

….Could indicate involvement of K+ or Cl-….

  1. Ion substitution
    Proves K+ not involved, it’s Cl-

….∴ Rs are Cl- channels….(GABAa Rs)
Cl- flows into cells when channels open (outward current bc current defined by flow of positive ions)

Causes hyper. –> IPSP

58
Q

GABAa Rs

Ag/Antag

A

Ligand-gated Cl- channels

Zolpidem/ambiem = GABAa agonist
Flumazenil = GABAa antagonist, antidote for OD
59
Q

Zolpidem/ambiem

A

GABAa agonist

60
Q

Flumazenil

A

GABAa antagonist

antidote for OD

61
Q

Fast v. slow synaptic transmission time comparison

A

Fast (10s of ms)

Slow (100s of ms - seconds)

62
Q

Fast v. slow synaptic transmission time comparison

A 
Fast: 
Direct NT binding
∴ syn. transmission quick (10s of ms)
Direct opening of ion channels
EPSP or IPSP
Can trigger AP

Slow:
Slower onset (10-100s of ms) and lasts longer (10s of ms to secs)
Indirect opening of ion channels -Mediated by metabo Rs
Usually small EPSP, mostly IPSP
Usually does not trigger AP
∴ regulates neuronal excitability

63
Q

Slow synaptic transmission steps

A
  1. NT binds to metabo. R
  2. Activates to G protein
  3. Activates primary effector
  4. 2nd messenger activated
  5. Activates secondary effectors
  6. (P) to produce effect
64
Q

Primary effectors

A

Enzymes that can change the 2nd messenger levels inside a cell; either produce or break down 2nd messengers

65
Q

The heart - what is it an example of?

A

Ex of slow synaptic transmission

♡ innervated by PS and S
S innervation: AP much faster, ♡faster, when excited
PS/vagus innervation: Less AP firing, ♡beat slower

BOTH responses caused by slow syn. transmission

S system: speeds it up

  • vagus nerve releases ACh
  • binds to m Ach R
  • dissociates trimeric G protein
  • Gβγ binds to GIRK channel and activates it
  • efflux of K+ creates hyperpolarization

PS system: slows it down

  • PS nerve releases E
  • Pacemaker cells have βadrinergic Rs
  • Activates G protein
  • Activates AC
  • ↑ cAMP production
  • (P) to many Ca2+ channels
66
Q

Efflux of K+ would be…

A

Outward current

67
Q

Influx of Cl- would be….

A

Cl- flows into cells when channels open (outward current bc current defined by flow of positive ions)

68
Q

cAMP pathway, IP3 pathway

A

Know steps, know how to dissect

69
Q

What does it mean the “fastest” slow syn. transmission?

A

G protein modulation of ion channels

ACh
I
Activation of Muscarinic ACh receptor (mAChR)
I
 Activation of G proteins
I
Direct activation of Kir channels by G
I
Hyperpolarization
70
Q

The phosphoinosital (PI) system - IP3 pathway

A

Many NTs activate this system, ex: ACh

PLC: effector/enzyme that breaks down PIP2
IP3 then ↑ [Ca2+] in cytosol

Shortcut: PIP2 can directly bind/activate some channels

71
Q

You stimulate a presynaptic terminal and elicit a fast EPSP, followed by a slow one. Explain how.

A

Fast EPSP elicited by fast synaptic transmission. Slow EPSP is by slow synaptic transmission.

Fast produced by N ACh Rs, can prove with curare or snake toxin block (wouldn’t affect slow response)

Slow produced by M ACh Rs - metabotropic cascade causing delay, can prove with hyocine block (wouldn’t affect fast)

72
Q

Ion channels are regulated by (in slow syn. transmission)

A

(P)
2nd messengers
G proteins
Intermediate signalling molecules

73
Q

Nicotinic vs. Muscarinic Rs

A

Nicotinic - ionotropic, fast chemical transmission

Muscarinic - metabotropic, slow chemical transmission

74
Q

Amplification

A

*GCPR can activate many G proteins

G protein can only bind 1:1

*Primary effector can bind many 2nd msngers

2nd msngr can only bind 1:1

*2nd effector can bind to many kinases

YOU CAN ALSO HAVE CROSS TALK TO AMPLIFY SIGNALING PATHWAY

75
Q

Properties of slow synaptic transmission

A 
 Mediated by metabotropic receptors
 Slow on and slow off
 Amplification
 Alteration of the biochemical (metabolic) state
 Crosstalk between signaling pathways
 No direct opening of ion channels
 Indirect opening or closing of ion channels
 Modulation of neuronal excitability

Neurobiology (6 decks)

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