Hp-Chazot: Cns Synaptic Transmission

Front 1

What are the two main nt in the brain?

Back 1

Glutamate - excitatory

GABA - inhibitory

Front 2

What are the different types of glutamate receptors?

Back 2

Ionotropic

Metabotropic

Front 3

Explain Glutamate Ionotropic receptors

When are they activated?

What do they allow the flow of?

What is the effect of activation?

Advantages?

Back 3

ligand-gatednonselective cation channel pores, activated when glutamate binds receptor.

Allowflow of K, Na and Ca2+.

Agonist stimulates EPSC, triggers AP ifenough receptors are activated.

Fast inrelaying info.

Front 4

Explain group I glutamate metabotropic receptor

Back 4

Stimulation causes PLC to hydrolyse phospholipids in plasma membrane to form IP3 and DAG.
IP3 - hypophilic, travels to ER, opens Ca channels. DAG remains in membrane - cofactor for activation of PKC.

Receptors are associated with Na/K channels. Can increase IPSPs

Front 5

Explain Glutamate Metabotropicreceptors

Back 5

Indirectly activate ion channels throughsignalling cascade – G proteins.

More prolonged stimulus.

Excitatorypostsynaptic current. EC region – binds glutamate, phosphorylation ofintracellular region.

Front 6

Where are glutamate receptors present?

Back 6

Dendritesof postsynaptic cells and astrocytes (glial cells) and Oligodendrocyte

Front 7

Are the receptors specific to glutamate?

Back 7

· Usually not specific – may require another agonist.

Front 8

Explain the Glutamate-gluatamine cycle?

Back 8

Ensures adequate supply of glutamate in CNS.

Neurones not able to synthesise glutamate and GABA from glucose.

Metabolic cycle, release of GABA and glutamate from neurones which are taken up by astrocytes.

In return, astrocytes release glutamine (non-neuroactive species)to be taken up by neurones for use as precursor to synthesise glutamate/GABA using glutamine synthetase pathway

Front 9

What type of receptor is the NMDA?

Back 9

· Ionotropic.

Front 10

Which ion binds to the NMDA receptor?

Back 10

· Internal binding site for an Mg2+ ion

At hyperpolarised membrane potentials, this ion blocks the channel - voltage-dependent block

Thus, the channel pass cations only during depolarisation.

Co-agonist glycine required for opening.

Front 11

Explain the requirements for activation of the receptor

Back 11

· So, rely on EPP produced by AMPA to open – not instantaneous.

Requires co-activation by two ligands – glutamate and D-serine/glycine.

Front 12

Which ion causes LTP and LTD?

Back 12

· Permeable to Ca2+ -causes LTP and LTDby transducing signalling cascades and regulating gene expression.

Front 13

What is another glutamate receptor?

Back 13

ionotropic

Front 14

What is LTP?

Back 14

repeated stimulationleads to enhanced stimulation

Front 15

Explain the process of LTP

Back 15

· Removal of Mg block of NMDA channel bydepolarisation

· Sustained glutamate release

· Activation of NMDA receptors

· Ca entry

· Activation of metabolic pathways - binds to calmodulin

· Protein phosphorylation

· Synthesis of NO - released from presynaptic terminal via retrograde signals

· Activation of CREB

Front 16

What is Excitotoxicity caused by?

Back 16

· Overstimulation – neurodegeneration and neuronaldamage, specifically NMDA receptors – causes high levels of Ca2+ toinflux into postsynaptic cell.

Front 17

Glutamate and Stroke

Back 17

Interruptionof blood supply to the brain. Cell death (necrosis) in the core

Excessiveglutamate release in penumbra

Sustainedactivation of glutamate receptors

Excitotoxicity –uncontrolled entry of Ca2+ andNa+

Cascadeof toxic metabolic events triggered by high [Ca2+]

Front 18

What does high Ca result in?

Back 18

Activates cascade of cell degradation – involves proteases, lipases, NO synthase – damagecell structures. Ingestion of excitotoxins (NMDA) – induce excitotoxicity – positionfeedback cell death.

Front 19

What diseases is excitotoxicity invovled in?

Back 19

Strokes, NDG disease, MS, Parkinson’s.

Front 20

How are receptors changed in synaptic plasticity?

Back 20

· Change in number of ionotropic receptors (addedby exocytosis and removed by endocytosis) leads to LTP in hippocampus andneocortex.

· Metabotropic glutamate receptors may modulatesynaptic plasticity by regulating postsynaptic protein synthesis through secondmessenger systems.

Front 21

What are other effects of synaptic plasticity?

Back 21

· Enhanced transmitter release

· Increased sensitivity

· Increased protein synthesis

Front 22

Name a drug acting on glutamate receptors

Back 22

· MK-801 – NMDA receptor antagonist which blocksexcitotoxicity. But induces psychotic episodes.

Front 23

What is the GABA receptor?

Back 23

· Inhibitory (main, 20% – brain), regulates muscletone. Synthesis: metabolite of glutamate or by amination of a-ketoglutaric acid(from TCA cycle)

Front 24

What are GABA drugs?

Back 24

· GABA-enhancing drugs are sedative, anaesthetic,anticonvulsant

Front 25

What are the different GABA receptors?

Back 25

A, B and C

Front 26

Explain the structure of GABA-A receptor

Back 26

ionotropic; pentameric; members of Cys loop family of receptors (inc.glycine, 5-HT).

16 different subunits.

Ligand-gated Cl channels. Cl entryhyperpolarises membrane (-65mV)- IPSP. Primarily post-synaptic

Front 27

Explain the structure of GABA-C receptor

Which drugs are the receptors insensitive to?

Back 27

ionotropic; primarily retinal; r-subunits.

Insensitiveto benzo/barbits.

Front 28

Explain the structure of GABA-B receptor

Back 28

Metabotropic effects; excitatory

Presynaptic and postsynaptic

- Stimulate K+ entry - hyperpolarise neurone, prevents Na opening.

- Reduce adenylyl cyclase activity and decrease cell's conductance to Ca

Slow response.

Front 29

What are GABA-A Receptor Modulators and what are the effects?

Back 29

Benzodiazepines- Anxiolytic, hypnotic, anticonvulsant.

·

Front 30

how does Benzodiazepines work?

Back 30

Potentiates GABA responses by increasingfrequency of Cl channel opening – agonists.

· Bind with high affinity to an accessory site onGABA-A receptor

· E.g. diazepam long duration of action 24-48 hrs– muscle relaxant.

Front 31

What are issues with Benzodiazepines?

Back 31

· Problems of tolerance and dependence

· Can cause anterograde and retrograde amnesia

Front 32

What is Benzodiazepines a safer alternative to?

Back 32

Barbiturates due to higher therapeutic ratio.

Front 33

What are Barbiturates?

Back 33

sedatives.

Potentiate GABA responses by prolonging Cl channel opening. But can openchannel without GABA – so no longer used therapeutically.

Front 34

Explain the GABA-B receptor

Back 34

· gamma-subunit required for benzodiazepine activity

· Different isoforms of subunits – combine to give different receptors

Front 35

Explain the GABA-A receptor

Back 35

· Activation – fast IPSP.

· Increase in Cl- conductance

· Studies – gene knockout, ablation of receptorsubunits - alpha1-point-mutated micediazepam-induced sedation and anticonvulsant effects were attenuated but othereffects were unaffected.

Front 36

What is the GABA-glutamine cycle?

Back 36

Glutamine is taken up by neurones and converted to glutamate, which is metabolised into GABA - glutamate decarboxylase.

Upon release, GABA is taken up into astrocytes and then catabolized into succinate. Glutamine is synthesized from succinate via the TCA cycle

Front 37

Does a low stimulus activate AMPA or NMDA receptors?

Back 37

AMPA only as NMDA receptors are blocked by Mg

Front 38

How can NMDA receptors be activated?

Back 38

Larger stimulus, AMPA depolarise membrane to expel Mg for NMDA