Synaptic Transmission

Question 1

What are the 4 criteria for a neurotransmitter?

Answer 1

• produced presynaptically
• released due to electrical stimulation
• produces physiological effect
• terminate activity

Question 2

What is a neurotransmitter?

Answer 2

Chemical used to transmit information from the presynaptic neuron to the postsynaptic neuron

Question 3

What does an ionotropic receptor do?

Answer 3

Opens an ion channel

Question 4

What does a metabotropic receptor do?

Answer 4

Activates an internal second messenger that affects functioning of postsynaptic cells

Question 5

What is an agonist?

Answer 5

Drug/neurotransmitter that combines with a receptor to produce a cellular reaction

Question 6

What is an antagonist?

Answer 6

Drug that completely or partially blocks the action of an agonist; no cellular effect after interacting with the receptor

Question 7

Name 3 things receptors vary in

Answer 7

• Kinetics (rate of transmitter binding/channel gating determine duration of effects)
• Selectivity (which ions fluxed)
• Conductance (rate of flux)

Question 8

Give an example of a metabotropic receptor

Answer 8

G-protein coupled receptor

Question 9

Metabotropic receptor

Answer 9

Activate internal 2nd messenger systems that go on to affect the functioning of the postsynaptic cells.

e.g. G-protein coupled receptors

Activation description:
* neurotransmitter binds to receptor and activates G-protein
* G protein splits and activates other enxymes
* Breakdown of GTP turns off G protein activity
* Series of chemical reactions lead to amplification of the signal (2nd messenger system)
= slow but larger effects

Question 10

Type of receptor, location, function, mechanism, stimulus

Autoreceptors

Answer 10

Typically G-protein coupled receptors located on the presynaptic terminal, that regulate the internal process controlling the synthesis and release of neurotransmitters via a negative feedback mechanism in response to neurotransmitters in the synaptic cleft.

Question 11

Classical neurotransmitters

Categories of neurotransmitters (1/2)

Answer 11

Neurotransmitters that are:
* synthesised locally in the presynaptic terminal
* stored in synaptic vesicles
* released in response to local increase in Ca2+

e.g. Amino acids (FAST transmission) such as GABA, glutamate
e.g. Monoamines
e.g. Acetylcholine

Question 12

Neuropeptides

Categories of neurotransmitters (2/2)

Answer 12

• synthesised in the cell soma and transported to the terminal
• stored in secretory glands
• released in response to global increase in Ca2+

e.g. endorphin (pain relief)

Question 13

Fast Synaptic Transmission

Answer 13

• glutamate ionotropic receptors flux Na+ which causes EPSP (excitatory post synaptic potential), depolarising the postsynaptic neuron = EXCITATORY
• GABA ionotropic receptors flux Cl- which causes IPSP (inhibitory post synaptic potential), hyperpolatising the postsynaptic neuron = INHIBITORY

Question 14

Glutamate

Answer 14

The major fast excitatory neurotransmitter in the CNS

• synthesised in presynaptic terminals from glucose or glutamine
• loaded and stored in vesicles by vesicular glutamate transporters
• released by exocytosis
• acts at glutamate receptors
• reuptake by excitatory amino acid transporters (EAATs)

3 glutamate ionotropic receptors:
* AMPA - fast opening
-binding of glutamate causes opening of sodium ion channel, causing depolarisation
-agonist is AMPA
-antagonists include CNQX and DNQX
* NMDA - slower opening
-permeable to sodium, potassium and calcium ions
-voltage-dependent blockade as has a magnesium ion block; this is pushed out when the membrane is depolarised and sodium/calcium ions can move in
-requires glycine (co-agonist)
-competitive agonist is NMDA
-competitive antagonist is AP5
-non-competitive antagonist is PCP
* Kainate - fast opening, similar to AMPA

Key takeaway is that NMDA receptors open when postsynaptic memberane is depolarised (i.e. when enough EPSPs have been generated due glutamate acting on AMPA receptors). Slow increase in depolarisation as glutamate acts on AMPA, then rapid increase as threshold passed for Mg2+ block to be removed from NMDA receptors.

Question 15

GABA

Answer 15

‘Gamma aminobutryic acid’; the major inhibitory neurotransmitter.

Activates an ionotropic receptor (GABAA) which opens a chloride channel, causing hyperpolarisation.

Too much GABA can cause sedation/coma; right dose of drugs increasing GABA transmission can be used to treat epilepsy; GABA metabolite used as date rape drug

• synthesised from glutamate
• loaded and stored in synapses by vesicular GABA transporter
• released by exocytosis
• acts at ionotropic GABAA and metabotropic GABAB receptors
• cleared from synapse by reuptake using transporters on glia and neurons (including non-GABAergic neurons)

2 main GABA receptor families:
* GABAA ionotropic receptors
-ligand-gated Cl- channel
-fast IPSPs
* GABAB metabotropic receptors
- G-protein coupled
-indirectly coupled to potassium or calcium ion channels through 2nd messengers (opens K+, closes Ca2+)
-slow IPSPs

Question 16

GABAA receptors

Answer 16

ionotropic, ligand-gated Cl- channel, fast IPSPs

complex receptor with multiple binding sites
* competing with GABA for same binding site: muscimol (agonist from mushroom), bicuculine/picrotoxin (antagonists)
* not competing with GABA: benzodiazapines, barbiturates, ethanol, neurosteroids

Drugs increasing GABA activity reduce anxiety (‘anxiolytic’) - agonists: alchohol, barbiturates; indirect agonist: benzodiazapines
* agonists produce IPSP on their own, but also enhance IPSP caused by GABA
* indirect agonist does not produce IPSP on their own, but enhances IPSP caused by GABA

Drugs decreasing GABA activity increase anxiety (‘anxiogenic’) - antagonists, fliumazenil
* antagonist does not have an effect on its own, but reduces the IPSP caused by GABA

Question 17

Neuromodulators

Answer 17

Do not carry primary information, but affect the response properties of neurons (e.g. excitability)

Include dopamine, serotonin, noradrenaline, acetylcholine

Diffuse modulatory systems: specific neuron populations that project diffusely and modulate the activity of glutamate and GABA neurons in their target areas

Question 18

Dopaminergic system

Diffuse modulatory system (1/3)

Answer 18

Dopamine neurons have their cell bodies in the midbrain and project into the forebrain

3 systems:
* nigrostriatal system; substantia nigra projections to the neostriatum; involved in movement; dysfunction can contribute to Parkinson’s (destruction of dopamine projections from SN to basal ganglia) or Huntington’s (destruction of dopamine target neurons in striatum)
* mesolimbic system; ventral tegmental area projections to nucleus accumbens; role in reinforcement; dysfunction can lead to addiction (abused drugs lead to enhanced dopamine release in NAcc)
* mesocortical system; ventral tegmental area projections to prefrontal cortex; role in working memory and planning; dysfunction can lead to schizophrenia

1. Dopamine synthesis: tyrosine catalysed by tyrosine hydroxylase to L-Dopa, which is catalysed by dopa decarboxylase to produce dopamine
2. Catecholamine storage (loaded into vesicles)

Drugs affecting dopamine synthesis/storage:
* Reserpine impairs storage of monoamines in synaptic vesicles
* L-DOPA used as treatment for Parkinson’s as it bypasses the rate-limiting step
* AMPT inactivates tyrosine (research drug, not therapeutic)

3. Dopamine release: Ca2+ dependent exocytosis
4. Dopamine reuptake: dopamine transporters (DATs), then reloaded into vesicles or enzymatically degraded by MAOs or COMTs

Drugs affecting dopamine release:
* stimulants: cocaine, amphetamine, ritalin - block reuptake of monoamines so more DA in synaptic cleft, thus extended action on postsynaptic neuron (amphetamine reverses DAT so pumps out DA in an uncontrolled release)
* selegiline (monoamine oxidase B inhibitor) and entacapone (COMT inhibitor) - prevent breakdown of catecholamines, increasing releasable pool of DA; can have antidepressant activity and can be used to treat Parkinson’s

Question 19

Serotonergic system

Diffuse modulatory system (2/3)

Answer 19

9 raphe nuclei in brainstem with diffuse projections, each to a different part of the brain:
* descending projections to the cerebellum and spinal cord (pain)
* ascending projections to the cerebral cortex (reticular activating system)
Raphe neurons fire tonically durin wakefulness and are quiet during sleep; they function in mood, sleep, pain, emotion and appetite.

1. Serotonin synthesis: tryptophan broken down by tryptophan hydroxylase into 5-hydroxytryptophan (5-HTP), which is broken down by aromatic amino acid decarboxylase into serotonin (5-HT)
2. Serotonin storage (loaded into vesicles)
3. Serotonin release (Ca2+ dependent exocytosis)
4. Serotonin reuptake/metabolism: by serotonin transporters (SERTs) on the presynaptic membrane, then degraded by MAOs

Drugs affecting serotonin release and reuptake:
* fluoxetine (prozac) blocks serotonin reuptake (is an SSRI) = antidepressant
* fenfluramine causes release of serotonin and inhibits reuptake = appetite suppressant
* MDMA reverses SERTs, releasing serotonin into synaptic cleft

Question 20

Cholinergic system

Diffuse modulatory system (3/3)

Answer 20

In the PNS: acetylcholine at neuromuscular junction and synapses in the autonomic ganglia

In the CNS:
* basal forebrain complex - projections to hippocampus and cortex
* pontomesencephalotegmental complex - cholinergic link between brainstem and basal forebrain complex

Cholinergic interneurons in the striatum and cortex

1. acetylcholine synthesis: made from choline
2. acetylcholine storage: loaded into vesicles
3. acetylcholine release: Ca2+ dependent exocytosis
4. acetylcholine metabolism: rapidly degraded into synaptic cleft by acetylcholinesterase, then choline is transported back into the presynaptic terminal and coverted back into acetylcholine

Drugs affecting acetylcholine release, storage and degradation:
* acetylcholinesterase inhibitors (e.g. Physostigmine) - block breakdown of ACh, causing extended action in the synaptic cleft
* botulinim - blocks docking of vesicles by attacking SNAREs, so no ACh release
* botox - acts directly at synapse in NMJ; muscles lose all input, becoming permanently relaxed
* tetanus toxins - retrogradely transported up at NMJ, work at inhibitory (glycine) synapses in cholinergic motor neurons of the spinal cord; inhibiting relase of glycine disinhibits the cholinergic neurons, so continuously fire causing permanent muscle contraction; also attack SNARE proteins