L7: Chemistry and Physiology of the Synapse

Question 1

What are the 3 types of ionotropic glutamate receptors?

Answer 1

1. NMDA
2. AMPA
3. Kainate

They respond to glutamate as a ligand

Question 2

Glutamate excitotoxicity

Answer 2

excessive Ca2+

Question 3

Gs

Answer 3

stimulates adenylyl cyclase

Question 4

Gi

Answer 4

inhibits adenylyl cyclase

Question 5

Gq

Answer 5

stimulates phospholipase C

Question 6

2 examples of receptors are Glutamate ionotropic receptors and GABA ionotropic receptors. Briefly describe their structure and action.

Answer 6

• Receptors form an ion channel
• contains central pore for ions to flow
• contains a binding site for a ligand

Action:

• Fast synaptic transmission
• Binding of ligand causes conformational change in protein, which opens the channel

Question 7

Glutamate ionotropic receptors

Answer 7

• flux Na+
• causes an EPSP (Excitatory Post Synaptic Potential)
• depolarizing postsynaptic neuron.
• fire an action potential.

Question 8

GABA ionotropic receptors

Answer 8

• flux Cl-
• causes an IPSP (Inhibitory Post Synaptic Potential) -hyperpolarizing postsynaptic neuron
• inhibits firing unless sufficient glutamate stimulation can counteract hyperpolarization.

Question 9

Ionotropic receptors

-examples

Answer 9

• Nicotinic
• 5HT
• ATP
• Glycine

Question 10

Synaptic integration

Answer 10

combination of all changes in membrane potential

considers both inhibitoty and excitatory inputs of cell and calculates overall potential

Question 11

Metabotropic Receptors

• structure
• function
• examples

Answer 11

• Use a 2nd messenger
• indirectly linked to ion channels
• causes cascade of metabolic reactions intracellularly

Examples

• GABA b
• Metabotropic Glu
• Beta adrenergic in the heart
• DA

Slower than ionotropic

Question 12

NMDA

• Agonist
• Antagonist

Answer 12

-Agonist
NMDA

-Antagonist
APV

Question 13

AMPA

• Agonist
• Antagonist

Answer 13

-Agonist
AMPA

-Antagonist
CNQX

Question 14

Kainate

• Agonist
• Antagonist

Answer 14

-Agonist
Kainic acid

-Antagonist
CNQX

Question 15

Non-NMDA receptors

Answer 15

-AMPA and Kainate

• Fast opening channels permeable to Na+ and K+
• Responsible for early phase EPSP

Question 16

NMDA receptor

Answer 16

Slow opening channel- late phase EPSP

-permeable to Ca2+ as well as Na+ and K+

• requires glycine
• neuroplasticity
• long term memory formation?

Question 17

Mechanism of NMDA receptors

Answer 17

• Non-selective ion channel
• requires glycine as cofactor
• Mg2+ blockade
• membrane has to already be depolariced (in the presence of glutamate) to release Mg2+
• flux of ions causes longer period of depolarisation.
• Ca2+ lead to activation of enzyme=NEUROPLASTICITY

Question 18

phencyclidine (PCP, angel dust) and MK801

Answer 18

Inhibits NMDA receptor

this blockade of NMDA produces symptoms like hallucinations in Schizophrenia.

Question 19

NMDA receptors and excitotoxcity

Answer 19

Excessive Ca2+ influx
-activates enzymes that degrade proteins

can lead to stroke, cardiac arrest etc.

Question 20

Nicotine

Excitatory or modulatory?

Answer 20

• excitatory at NMJ

- excitatory or modulatory in the CNS

Question 21

5HT

Excitatory or modulatory?

Answer 21

Excitatory or modulatory

Question 22

ATP

Excitatory or modulatory?

Answer 22

Excitatory

Question 23

How do antipsychotics work?

Answer 23

enhance flow through NMDA channel

Question 24

Autoreceptors

Answer 24

Modulation at the presynaptic level

regulates release of NT
“Give less”

Question 25

Heteroreceptors

Answer 25

modulation at the presynaptic level

regulates synthesis of NT
“Make less”

Question 26

How can you control transmission at the postsynaptic level?

Answer 26

Change transmission firing pattern
Directly at ligand gated ion channels or indirectly at GPCR
Neuroplasticity

Question 27

Enzyme linked receptors

-give example

Answer 27

Tyrosine kinase
Neutrotrophin binding (eg NGF)
Autophosphorylate on activation
downstream cascade

Question 28

3 properties of LTP

Answer 28

Temporal - summation of inputs leads to threshold

Associative- Simultaneous stimulation of strong and weak pathway = induce LTP in both pathways

Input Specific- LTP at one synapse not propagated to adjacent synapse

Question 29

AMPA

• At resting potential
• during depolarisation

Answer 29

At RP: few AMPA
AMPA receptor is activated by Glutamate 
Allows influx of Na+ ions 
Influx of ions (EPSC) creates EPSP 
EPSP NOT sufficient to release of Mg2+ block or cause AP

Depolarisation:
more AMPA

Question 30

NMDA receptor

• At resting potential
• during depolarisation

Answer 30

At RP:
NMDA receptor IS NOT ACTIVATED as Mg2+ block
NO influx of Na+ AND Ca2+ ions
Result = Small EPSP = NO AP

Depolarization:

Question 31

What is the effect when Ca2+ goes through NMDA channel

Answer 31

• Ca2+ activates NO synthase
• activates guanlyl cyclase
• produces 2nd messenger cGMP
• leads to increased Glu release

Question 32

early phase LTP (acquisition)

Answer 32

When Glutamate binds NMDA on strongly depolarized post synaptic membrane (-40mV)
Ca2+ influx through NMDA receptors
Ca2+ binds to Calmodulin
Calmodulin activates CaMKII + PKC

Result = more AMPA + more efficient AMPAs = more EPSP = easier to induce AP

Question 33

Late phase LTP (consolidation)

Answer 33

-Need protein synthesis + gene transcription
-Insertion of AMPA receptors in early LTP at synapse INDEPENDENT of protein synthesis
Leads to phosphorylation of transcription factors such as CREB-1

Question 34

Long Term Depression (LTD)

Answer 34

Same players as LTP involved but slight differences:

1. Still an NMDA-dependent process
2. Triggered by lower levels of NMDA receptor activation = prolonged low level rises in Ca2+
3. Ca2+ activated phosphatases rather than kinases
4. Phosphatases lead to:
   - AMPA receptors being removed from membrane and being dephosphorylated