Topic 8 Neural communication

Why nervous systems?

Escherichia Coli (E. Coli)

  • Tiny, single-celled bacterium
  • Feeds on glucose
  • Chemosensory (“taste”) receptors on surface membrane
  • Flagellum for movement
  • Food concentration regulates duration of “move” phase
  • ~4 ms for chemical signal to diffuse from anterior/posterior

Figure 8.1: https://www.youtube.com/embed/QGAm6hMysTA?rel=0

Paramecium

  • 300K larger than E. Coli
  • Propulsion through coordinated beating of cilia
  • Diffusion from head to tail ~40 s!
  • Use electrical signaling instead
    • \(Na^+\) channel opens (e.g., when stretched)
    • Voltage-gated \(Ca^{++}\) channels open, \(Ca^{++}\) enters, triggers cilia movement
    • Voltage propagates along cell membrane within ms

Caenorhabditis Elegans (C. Elegans)

  • ~\(10x\) larger than paramecium
  • multi-cellular (\(n=959\) cells total)
  • \(n=302\) are neurons & \(n=56\) are glia
  • nervous system 37% of cells vs. ~0.5% in humans
  • Can swim, forage, mate

Figure 8.2: https://www.youtube.com/embed/GgZHziFWR7M?rel=0

  • Bigger bodies (need to process specific info, move through water, air, on land)
  • For neurons (point to point communication)
  • Live longer
  • Do more, do it faster, over larger distances & longer time periods

Nervous systems are communication systems

  • Chemical communication : short distances
    • Cheap, energy-efficient, “compute with chemistry”
  • Electrical communication : long distances
    • More “expensive”/less energy-efficient
  • Synaptic communication
    • Chemical (via neurotransmitters)
    • Electrical (via ion flow)
  • Endocrine communication (chemical via hormones)

Synaptic communication

Action potential propagates from soma

  • Soma receives input from dendrites
  • Axon hillock sums/integrates
  • If sum > threshold, AP “fires”
Synaptic summation: https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/1224_Post_Synaptic_Potential_Summation.jpg/512px-1224_Post_Synaptic_Potential_Summation.jpg

Figure 8.3: Synaptic summation: https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/1224_Post_Synaptic_Potential_Summation.jpg/512px-1224_Post_Synaptic_Potential_Summation.jpg

Action potential arrival at synapse triggersneurotransmitter (NT) release

  • Voltage-gated calcium Ca++ channels open
  • Ca++ causes synaptic vesicles to bind with presynaptic membrane & merge with it
  • NTs released via exocytosis
[[@Hastoy2017-it]](https://doi.org/10.1016/j.ceca.2017.10.005)

Figure 8.4: (Hastoy et al. 2017)

[[@Hastoy2017-it]](https://doi.org/10.1016/j.ceca.2017.10.005)

Figure 8.5: (Hastoy et al. 2017)

NTs diffuse across synaptic cleft & bind to next neuron

  • NTs bind with receptors on postsynaptic membrane
  • Receptors respond
  • NTs unbind, are inactivated
Synapse: https://upload.wikimedia.org/wikipedia/commons/thumb/3/30/SynapseSchematic_en.svg/512px-SynapseSchematic_en.svg.png

Figure 8.6: Synapse: https://upload.wikimedia.org/wikipedia/commons/thumb/3/30/SynapseSchematic_en.svg/512px-SynapseSchematic_en.svg.png

[[@Haucke2011-ub]](http://dx.doi.org/10.1038/nrn2948)

Figure 8.7: (Haucke, Neher, and Sigrist 2011)

Why do NTs move from presynaptic terminal toward postsynaptic cell?

  • Electrostatic force pulls them

  • Force of diffusion

  • Neural membrane ~8 nm

  • Synaptic vesicles ~40-60 or ~90-120 nm

  • Synaptic cleft ~15-50 nm

  • Synaptic 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)
  • 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

  • Receptors generate postsynaptic potentials (PSPs)
    • Small voltage changes
    • Amplitude scales with # of receptors activated
    • Number of receptors activated ~ # of vesicles released
http://pittmedneuro.com/synaptic.html

Figure 8.8: http://pittmedneuro.com/synaptic.html

Two types of postsynaptic potentials

  • 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

NT inactivated by multiple mechanisms

  • Buffering
  • 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)

Why must NTs be inactivated?

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

Types of synapses

Synapse types: https://upload.wikimedia.org/wikipedia/commons/thumb/3/33/Blausen_0843_SynapseTypes.png/512px-Blausen_0843_SynapseTypes.png

Figure 8.9: Synapse types: https://upload.wikimedia.org/wikipedia/commons/thumb/3/33/Blausen_0843_SynapseTypes.png/512px-Blausen_0843_SynapseTypes.png

  • 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))
https://www.britannica.com/science/neurotransmitter

Figure 8.10: https://www.britannica.com/science/neurotransmitter

Neurotransmitters

https://www.compoundchem.com/2015/07/30/neurotransmitters/

Figure 8.11: https://www.compoundchem.com/2015/07/30/neurotransmitters/

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

Amino acids

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

Glutamate

  • Primary excitatory NT in CNS (~ 1/2 all synapses)
  • Role in learning (via NMDA receptor)
  • Transporters on neurons and glia (astrocytes and oligodendrocytes)
  • Linked to umami (savory) taste sensation, think monosodium glutamate (MSG)
  • Dysregulation in schizophrenia (McCutcheon, Krystal, and Howes 2020), mood disorders (Małgorzata et al. 2020)
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+

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)
Acetylcholine receptor: https://cdn.britannica.com/41/54741-004-8E4F81CC/acetylcholine-receptor-channel-subunits-diffusion-ions-sodium.jpg?w=300&h=300

Figure 8.12: Acetylcholine receptor: https://cdn.britannica.com/41/54741-004-8E4F81CC/acetylcholine-receptor-channel-subunits-diffusion-ions-sodium.jpg?w=300&h=300

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

Monoamines

Family Neurotansmitter
Monoamines Dopamine (DA)
Norepinephrine (NE)/Noradrenaline (NAd)
Epinephrine (Epi)/Adrenaline (Ad)
Serotonin (5-HT)
Melatonin
Histamine

Dopamine (DA)

  • Released by two pathways that originate in the midbrain tegmentum
    • Substantia nigra -> striatum, meso-striatal projection
    • Ventral tegmental area (VTA) -> nucleus accumbens, ventral striatum, hippocampus, amygdala, cortex; meso-limbo-cortical projection
Dopamine pathways: https://upload.wikimedia.org/wikipedia/commons/thumb/d/d8/Dopaminergic_pathways.svg/1200px-Dopaminergic_pathways.svg.png

Figure 8.15: Dopamine pathways: https://upload.wikimedia.org/wikipedia/commons/thumb/d/d8/Dopaminergic_pathways.svg/1200px-Dopaminergic_pathways.svg.png

  • DA Disruption linked to
    • Parkinson’s Disease (mesostriatal)
      • DA agonists treat (agonists facilitate/increase transmission)
    • ADHD (mesolimbocortical)
    • Schizophrenia (mesolimbocortical)
      • DA antagonists treat
    • Addiction (mesolimbocortical)
  • DA Inactivated by
https://doi.org/10.1016/bs.vh.2014.12.009

Figure 8.16: https://doi.org/10.1016/bs.vh.2014.12.009

Type Receptor Comments
Metabotropic D1-like (D1 and D5) more prevalent
D2-like (D2, D3, D4) target of many antipsychotics (drugs that treat schizophrenia symptoms)

Norepinephrine (NE)

  • Role in arousal, mood, eating, sexual behavior
  • Released by
Locus coeruleus: https://upload.wikimedia.org/wikipedia/commons/6/6d/Locus-coeruleus.gif

Figure 8.17: Locus coeruleus: https://upload.wikimedia.org/wikipedia/commons/6/6d/Locus-coeruleus.gif

  • Released by Sympathetic Nervous System (SNS) onto targets in PNS

  • Monoamine oxidase (MAO) inactivates monoamines in neurons, glial cells
  • Monoamine oxidase inhibitors (MAOIs) increase NE, DA
    • Inhibiting inactivation ~ -(-1) = + 1
  • Treatment for depression, but side effects (dry mouth, nausea, headache, dizziness)
https://www.nrronline.org/article.asp?issn=1673-5374;year=2020;volume=15;issue=6;spage=1006;epage=1013;aulast=Bari

Figure 8.18: https://www.nrronline.org/article.asp?issn=1673-5374;year=2020;volume=15;issue=6;spage=1006;epage=1013;aulast=Bari

Type Receptor Comments
Metabotropic \(\alpha\) (1,2) antagonists treat anxiety, panic
\(\beta\) (1,2,3) ‘beta blockers’ in cardiac disease

Serotonin (5-HT)

  • Released by raphe nuclei in brainstem
  • Role in mood, sleep, eating, pain, nausea, cognition, memory
  • Modulates release of other NTs
  • Most of body’s 5-HT regulates digestion
    • via Enteric Nervous System (in PNS)
https://en.wikipedia.org/wiki/Serotonin_pathway

Figure 8.19: https://en.wikipedia.org/wiki/Serotonin_pathway

[[@Furness2012-dy]](http://dx.doi.org/10.1038/nrgastro.2012.32)

Figure 8.20: (Furness 2012)

  • 5-HT receptors
    • Seven families (5-HT 1-7) with 14 types
    • All but one metabotropic
  • Ecstasy (MDMA) disturbs serotonin
  • So does LSD
  • Fluoxetine (Prozac)
    • Selective Serotonin Reuptake Inhibitor (SSRI)
    • Inhibits reuptake -> increases extracellular concentration
    • Treats depression, panic, eating disorders, others
  • 5-HT3 receptor antagonists are anti-mimetics used in treating nausea

Melatonin

  • Hormone released by pineal gland into bloodstream
  • Concentrations vary over the day, peak near bedtime
  • Release regulated by inputs from hypothalamus
http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/otherendo/pinealgland.jpg

Figure 8.21: http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/otherendo/pinealgland.jpg

Pineal gland: https://upload.wikimedia.org/wikipedia/commons/6/6d/Pineal_gland.gif

Figure 8.22: Pineal gland: https://upload.wikimedia.org/wikipedia/commons/6/6d/Pineal_gland.gif

Histamine

  • In brain, released by hypothalamus, projects to whole brain
    • Metabotropic receptors
    • Role in arousal/sleep regulation
  • In body, part of immune response
https://www.nature.com/articles/nrn1034

Figure 8.23: https://www.nature.com/articles/nrn1034

Other NTs

  • Gases
    • Nitric Oxide (NO), carbon monoxide (CO)
  • Neuropeptides
    • Substance P and endorphins (endogenous morphine-like compounds) have role in pain
    • Orexin/hypocretin, project from lateral hypothalamus across brain, regulate appetite, arousal
  • Neuropeptides (continued)
    • Cholecystokinin (CCK) stimulates digestion
    • Oxytocin and vasopressin released by posterior hypothalamus onto posterior pituitary, regulate social behavior

Non-chemical communication between neurons

  • Gap junctions
  • Electrical coupling
  • Connect cytoplasm directly
Gap junction: https://upload.wikimedia.org/wikipedia/commons/thumb/b/b7/Gap_cell_junction-en.svg/2000px-Gap_cell_junction-en.svg.png

Figure 8.24: Gap junction: https://upload.wikimedia.org/wikipedia/commons/thumb/b/b7/Gap_cell_junction-en.svg/2000px-Gap_cell_junction-en.svg.png

  • Fast, but fixed, hard to modulate
  • Examples, retina, cardiac muscle

Ways to think about synaptic communication

  • Specificity: point-to-point vs. broadcast
  • Direct (immediate) action vs. (delayed, prolonged) modulatory
  • Agonists vs. antagonists

Agonists vs. Antagonists

  • Agonists
    • bind to receptor
    • mimic action of endogenous chemical
  • Antagonists
    • bind to receptor
    • block/impede action of endogenous chemical

Valium is a GABA-A receptor agonist. This means:

  • It decreases inhibition
  • It activates a metabotropic Cl- channel
  • It facilitates/increases inhibition
  • It blocks an ionotropic channel

References

Anderson, Christopher M., and Raymond A. Swanson. 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.
Furness, John B. 2012. “The Enteric Nervous System and Neurogastroenterology.” Nature Reviews. Gastroenterology & Hepatology 9 (5): 286–94. https://doi.org/10.1038/nrgastro.2012.32.
Hastoy, Benoit, Anne Clark, Patrik Rorsman, and Jochen Lang. 2017. “Fusion Pore in Exocytosis: More Than an Exit Gate? A \(\beta\)-Cell Perspective.” Cell Calcium 68 (December): 45–61. https://doi.org/10.1016/j.ceca.2017.10.005.
Haucke, Volker, Erwin Neher, and Stephan J Sigrist. 2011. “Protein Scaffolds in the Coupling of Synaptic Exocytosis and Endocytosis.” Nature Reviews. Neuroscience 12 (3): 127–38. https://doi.org/10.1038/nrn2948.
Małgorzata, Panek, Kawalec Paweł, Malinowska Lipień Iwona, Tomasz Brzostek, and Pilc Andrzej. 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, Robert A, John H Krystal, and Oliver D Howes. 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.