2022-02-15 08:16:48

Prelude (4:13)

Prelude (4:44)

Today’s Topics

  • How neurons talk to one another
    • Synaptic communication
  • Neurotransmitters

How neurons talk to one another

In the beginning

  • Soma receives input from dendrites
  • Axon hillock sums/integrates
  • If sum > threshold, AP “fires”

Illustration of summation

1224 Post Synaptic Potential Summation

Steps in synaptic transmission

  • Rapid change in voltage triggers neurotransmitter (NT) release
  • Voltage-gated calcium Ca++ channels open
  • Ca++ causes synaptic vesicles to bind with presynaptic membrane & merge with it
  • NTs released via exocytosis

Steps in synaptic transmission

  • NTs diffuse across synaptic cleft
  • NTs bind with receptors on postsynaptic membrane
  • Receptors respond
  • NTs unbind, are inactivated

Synaptic transmission

SynapseSchematic en

Exocytosis

Why do NTs move from presynaptic terminal toward postsynaptic cell?

  • Electrostatic force pulls them
  • Force of diffusion

Why do NTs move from presynaptic terminal toward postsynaptic cell?

  • Electrostatic force pulls them
  • Force of diffusion

Relative sizes

  • Neural membrane ~8 nm
  • Synaptic vesicles ~40-60 or ~90-120 nm
  • Synaptic cleft ~15-50 nm
  • Cleft small relative to vesicles, so diffusion time short (< 0.5 ms)

Postsynaptic receptor types

  • Ionotropic (receptor + ion channel)
    • Ligand-gated
    • Open/close ion channel
    • Ions flow in/out depending on membrane voltage and ion type
    • Fast-responding (< 2 ms), but short-duration effects (< 100 ms)

Postsynaptic receptor types

  • Metabotropic (receptor only, no attached ion channels
    • Trigger G-proteins attached to receptor
    • G-proteins activate 2nd messengers
    • 2nd messengers bind to, open/close adjacent channels or change metabolism
    • Slower, but longer-lasting effects

Receptor types

Receptors generate postsynaptic potentials (PSPs)

  • Small voltage changes
  • Amplitude scales with # of receptors activated
  • Number of receptors activated ~ # of vesicles released

Postsynaptic potential types

  • Excitatory PSPs (EPSPs)
    • Depolarize neuron (make more +)
    • Move membrane potential closer to threshold
  • Inhibitory (IPSPs)
    • Hyperpolarize neuron (make more -)
    • Move membrane potential away from threshold

Mechanisms of NT inactivation

  • Buffering
    • e.g., glutamate into astrocytes (Anderson & Swanson, 2000)
  • Reuptake via transporters
    • molecules in membrane that move NTs inside
    • e.g., serotonin via serotonin transporter (SERT)
  • Enzymatic degradation
    • e.g., Acetylcholinesterase (AChE) degrades acetylcholine (ACh)

Questions to ponder

  • Why must NTs be inactivated?

Questions to ponder

  • Why must NTs be inactivated?
    • Keeps messages discrete, localized in time and space

What sort of PSP would opening a Na+ channel produce?

  • Excitatory PSP, Na+ flows in
  • Excitatory PSP, Na+ flows out
  • Inhibitory PSP, Na+ flows in
  • Inhibitory PSP, Na+ flows out

What sort of PSP would opening a Na+ channel produce?

  • Excitatory PSP, Na+ flows in
  • Excitatory PSP, Na+ flows out
  • Inhibitory PSP, Na+ flows in
  • Inhibitory PSP, Na+ flows out

What sort of PSP would opening a Cl- channel produce?

Remember [Cl-out]>>[Cl-in]; Assume resting potential ~60 mV

  • Excitatory PSP, Cl- flows in
  • Excitatory PSP, Cl- flows out
  • Inhibitory PSP, Cl- flows in
  • Inhibitory PSP, Cl- flows out

What sort of PSP would opening a Cl- channel produce?

Remember [Cl-out]>>[Cl-in]; Assume resting potential ~-60 mV

  • Excitatory PSP, Cl- flows in
  • Excitatory PSP, Cl- flows out
  • Inhibitory PSP, Cl- flows in
  • Inhibitory PSP, Cl- flows out

Types of synapses

Blausen 0843 SynapseTypes

Types of synapses

  • Axodendritic (axon to dendrite)
  • Axosomatic (axon to soma)
  • Axoaxonic (axon to axon)
  • Axosecretory (axon to bloodstream)

Synapses on

  • dendrites
    • usually excitatory
  • cell bodies
    • usually inhibitory
  • axons
    • usually modulatory (change p(fire))

Summary of chemical communication

Neurotransmitters

What are they?

  • Chemicals produced by neurons
  • Released by neurons
  • Bound by neurons and other cells
  • Send messages (have physiological effect on target cells)
  • Inactivated after release

Neurotransmiters

Family Neurotansmitter
Amino acids Glutamate (Glu)
Gamma aminobutyric acid (GABA)
Glycine
Aspartate

Glutamate

Glutamate

Type Receptor Esp Permeable to
Ionotropic AMPA Na+, K+
Kainate
NMDA Ca++
Metabotropic mGlu

\(\gamma\)-aminobutyric Acid (GABA)

  • Primary inhibitory NT in CNS
  • Excitatory in developing CNS, [Cl-] in >> [Cl-] out
  • Binding sites for benzodiazepines (e.g., Valium), barbiturates, ethanol, etc.
  • Synthesized from glutamate
  • Inactivated by transporters

Type Receptor Esp Permeable to
Ionotropic GABA-A Cl-
Metabotropic GABA-B K+

GABA

Other amino acid NTs

  • Glycine
    • Spinal cord interneurons
    • Also inhibitory
  • Aspartate
    • Like Glu, stimulates NMDA receptor

Acetylcholine (ACh)

  • Primary NT of CNS output
  • Somatic nervous system (neuromuscular junction)
  • Autonomic nervous system
    • Sympathetic branch: preganglionic neuron
    • Parasympathetic branch: pre/postganglionic
  • Inactivation by acetylcholinesterase (AChE)

ACh anatomy

Acetylcholine

Type Receptor Esp Permeable to Blocked by
Ionotropic Nicotinic (nAChR) Na+, K+ e.g., Curare
Metabotropic Muscarinic (mAChR) K+ e.g., Atropine

Curare

Atropine

How to stop your prey

Substance Effect
Japanese pufferfish toxin Blocks voltage-gated Na+ channels
Black widow spider venom Accelerates presynaptic ACh release
Botulinum toxin (BoTox) Prevents ACh vesicles from binding presynaptically
Sarin nerve gas Impedes ACh breakdown by AChE
Pesticides Impede AChE
Tetanus toxin Blocks release of GABA, glycine

Next time…

  • More on NTs!

References

acapellascience. (2017, June). The molecular shape of you (ed sheeran parody) | a capella science. Youtube. Retrieved from https://www.youtube.com/watch?v=f8FAJXPBdOg

Anderson, C. M., & Swanson, R. A. (2000). Astrocyte glutamate transport: Review of properties, regulation, and physiological functions. Glia, 32(1), 1–14. https://doi.org/10.1002/1098-1136(200010)32:1<1::AID-GLIA10>3.0.CO;2-W

Byrne, D. (2018, March). David byrne - here (official audio). Youtube. Retrieved from https://www.youtube.com/watch?v=T5TdD3eZjnM

Hastoy, B., Clark, A., Rorsman, P., & Lang, J. (2017). Fusion pore in exocytosis: More than an exit gate? A \(\beta\)-cell perspective. Cell Calcium, 68, 45–61. https://doi.org/10.1016/j.ceca.2017.10.005

Haucke, V., Neher, E., & Sigrist, S. J. (2011). Protein scaffolds in the coupling of synaptic exocytosis and endocytosis. Nature Reviews. Neuroscience, 12(3), 127–138. https://doi.org/10.1038/nrn2948

Małgorzata, P., Paweł, K., Iwona, M. L., Brzostek, T., & Andrzej, P. (2020). Glutamatergic dysregulation in mood disorders: Opportunities for the discovery of novel drug targets. Expert Opinion on Therapeutic Targets, 24(12), 1187–1209. https://doi.org/10.1080/14728222.2020.1836160

McCutcheon, R. A., Krystal, J. H., & Howes, O. D. (2020). Dopamine and glutamate in schizophrenia: Biology, symptoms and treatment. World Psychiatry: Official Journal of the World Psychiatric Association, 19(1), 15–33. https://doi.org/10.1002/wps.20693