Neurophysiology Lecture 4

Lecture 4; The Synapse

How a neuron gets to the synaptic cleft

1) Neuron sits there having inherit charge

• Called Resting Membrane Potential (RMP)

2) Depolarization event occurs

• Threshold event generates an AP to move across the axon

3) AP reaches the terminus, or a synapse

• Where the presynaptic neuron meets the postsynaptic neuron for communication

At the synapse/terminus there are ligands called __________ which bind to ligand gated channels on the postsynaptic neuron to open them

Neurotransmitters, the chemical signal at synapses

The axon terminus makes neurotransmitters and stores them in _________.

What are the two primary NTs found in the PNS? What about in the CNS?

Vesicles

Acetylcholine (ACh) and Norepinephrine (NE)

There are many different types of NTs in the CNS

One type of neuron usually makes one class/family of NTs.

Name the first major neurotransmitter family

1) Amino Acids

• GABA

• Glycine

• Glutamate

  • Usually only one of these is made at a terminus

One type of neuron usually makes one class/family of NTs.

Name the first second neurotransmitter family

2) Acetyl Choline

• ACh

One type of neuron usually makes one class/family of NTs.

Name the first third neurotransmitter family

3) Amines

• Serotonin

• Dopamine

• Norepinephrine

• Epinephrine

  • Amino acids strung together, or modified amino acids

  • Chemicals with nitrogen on them 

One type of neuron usually makes one class/family of NTs.

Name the fourth major neurotransmitter family

4) Neuropeptides

• Oxytocin

• Vasopressin

• Neuropeptide Y

  • Short guys

How are NTs released at the synaptic cleft?

1) When an AP reaches the axon terminus, ______-_____ ____ channels open

2) ____ enters cell

3) Stimulates a series of biochemical events that triggers the _______ of NT _______

• NT is released into the cleft

Voltage-gated calcium channels open

Ca2+

Exocytosis of NT vesicles

After the NT is released, how is the post-synaptic cell stimulated?

NT binds to different _______ ________ on ____-________ membrane

receptor proteins on post-synaptic membrane

• This stimulates something to happen, like a graded potential in the postsynaptic membrane

Example: ACh binds to ACh receptors on postsynaptic membrane (AChR)

Name the 2 main neurotransmitter receptor types

1) Ligand-gated ion channels

• Nicotinic AChR

2) Receptors acting through G-proteins 

• Muscarinic AChR

NOTE: There are others, which lead to ± changes in the RMP of the post-synaptic membrane

• graded potentials

  • a small, temporary change in a neuron's membrane potential that varies in strength  depending on the stimulus 

All signal transduction mechanisms for all cells have the same steps; what are they?

1) Lipid-soluble molecule binds intracellular receptor (R; enzyme, gene regulator)

2) R has enzymatic activity

3) R activates a separate enzyme 

4) Receptor is an ion channel

5) Receptor acts through G-protein to activate enzyme/ion channel

Ionotropic Channels are ______-_____ ___ _________ and use ______ gating

Ligand-gated ion channels; direct gating

Ex: AMPA, NMDA, Nicotinic ACh receptors

Metabotropic channels are _- _______ ______ and use _______ gating

G-protein coupled; indirect gating

Ex: mGluRs, Muscarinic ACh receptors

Once at the post-synaptic cell, do synapses always excite?

No! It depends on the type of neuron and the neurotransmitter

In excitatory synapses

1) What types of channels open?

2) Does this promote depolarization or hyperpolarization?

3) What is all of this called?

4) Name an example and where it is found

1) Stimulation of post-synaptic membrane leads to the opening of ligand-gated Na+ or Ca + channels 

2) This promotes depolarization, or the excitation of the membrane

• Charge becomes less negative and favors the formation of an AP

3) Excitatory Post-Synaptic Potential (EPSP); a graded potential

4) Example: Nicotinic AChR at the NMJ

In inhibitory synapses

1) What types of channels open?

2) Does this promote depolarization or hyperpolarization?

3) What is all of this called?

4) Name an example and where it is found

1) Stimulation of the post-synaptic membrane opens K+ or Cl- channels

2) This causes hyperpolarization

• Charge becomes more negative, may prevent an AP

3) Inhibitory Post-Synaptic Potential (IPSP); a graded potential

4) GABA Receptors in CNS

• Ligand-gated Cl- channels

What is summation in regard to IPSPs and EPSPs?

When the depolarization and hyperpolarization of graded potentials are added up over space and time to try and influence whether or not an AP is produced at the axon hillock

• Must depolarize to -55 for AP to result 

Overall summary of synapse activity

1) AP arrives at axon terminal

2) Ca2+ channels open

3) Ca2+ diffused in from ECF

4) NT release by exocytosis

• Most vesicles go to post, some go to pre

5) NT diffuses across synaptic cleft

• MUST drift across and bind to receptors (in some diseases they are stuck)

6) NT-Receptor Complex opens specific ion channels

7) Postsynaptic potenial generated 

• Can be positive OR negative

  • If inhibitory, makes downstream more negative

  • If excitatory, makes the downstream more positive

8) Local currents spread in all directions along cell membrane 

After NTs have generated a post-synaptic response, there are 3 things that can happen.

This is dependent on the NT and type of neuron.

What is the first outcome?

1) ACh is broken down into acetic acid and choline by acetylcholinesterase 

• Choline is taken up by presynaptic neuron and reused

When ACh diffuses, its a race to bind to a receptor before its half life expires

• If it is too slow, acetylcholinesterase binds to the receptor so it doesn’t release anymore

After NTs have generated a post-synaptic response, there are 3 things that can happen.

This is dependent on the NT and type of neuron.

What is the second outcome?

2) Most amine NTs (NE, dopamine, seratonin) are taken up by the pre-synaptic neuron (re-uptake) and re-used

• Some is broken down by specific enzymes in axon terminus

After NTs have generated a post-synaptic response, there are 3 things that can happen.

This is dependent on the NT and type of neuron.

What is the third outcome?

Some types diffuse away from synapse (GABA, glycine, glutatamate) to be metabolized by astrocytes 

Explain how organophosphates (poisons) damage the body in relation to ACh

Organophosphates inhibit acetylcholinesterase, causing a buildup of ACh in the cleft

• Causes the animal to have an excessive cholinergic response (salivating, vomiting) along with muscular problems 

In pharmacology, where in the synapse are important sites for drug targeting?

Give two examples example

Ion channels at synapses

Many anesthetics and sedatives alter the function of Cl- channels in the brain

• e.g. GABA receptors

SSRIs - re-uptake inhibitors

• Stop the re-uptake of NTs into the presynaptic cleft so you get more activation of downstream neurons

Drugs and toxins act at synapses too

Give some examples of toxins and mechanisms by which they act

Organophosphates, sarin, curare, atropine, strychnine, tensilon, neostigmine

Mechanisms

• Block release of NT (botulism, tetanus toxins)

• Block re-uptake of NT (SSRI, SBARI)

• Block receptor (Atropine)

• Block metabolism (Sarin, Organophosphates, Tensilon)

Another type of synapse is an _______ synapse.

How does it work?

Electrical synapse

Some gap junction proteins in neighboring cells are specialized

• When in contact, they open forming water-filled pores between the cells

• Depolarizations sweep from cell-to-cell as if it were one cell

Electrical synapses are fast, involuntary, uniform, and controlled; based on this, where in the body would this type of synapse occur?

This happens the most in cardiac muscle and conduction pathways

• Cells do not communicate via a chemical synapse, so electrical is a lot faster