PSY 511

Cells of the nervous system

Fun

http://www.gregadunn.com/ 

Cellular neuroanatomy

How many neurons and glia?

• Old “lore”: ~100 billion neurons
• New estimate (Azevedo et al., 2009):
  • ~86 +/- 8 billion neurons
  • 85 +/- 9 billion glia

“These findings challenge the common view that humans stand out from other primates in their brain composition and indicate that, with regard to numbers of neuronal and nonneuronal cells, the human brain is an isometrically scaled-up primate brain.”

(Azevedo et al., 2009)

(Azevedo et al., 2009)

Glia (neuroglia)

• Functions
  • Structural support
  • Metabolic support
  • Brain development

Astrocytes

• “Star-shaped”
• Probably most numerous cell type in CNS
• Physical and metabolic support
  • Support blood/brain barrier
  • Regulate local blood flow

https://en.wikipedia.org/wiki/Astrocyte

https://en.wikipedia.org/wiki/Astrocyte

• Interact with neurons
  • Ion (Ca++/K+) buffering
  • Neurotransmitter (e.g., glutamate) buffering

https://en.wikipedia.org/wiki/Astrocyte

• Shape brain development, contribute to synaptic plasticity
• Disruption linked to cognitive impairment, disease (Chung, Welsh, Barres, & Stevens, 2015)

Myelinating cells

Oligodendrocytes

• In brain and spinal cord (CNS)
• 1:many neurons

https://en.wikipedia.org/wiki/Oligodendrocyte

Schwann cells

• In PNS
• 1:1 neuron
• Facilitate neuro-regeneration

https://en.wikipedia.org/wiki/Schwann_cell

• Mnemonics: COPS/SPOC

Microglia

• Phagocytosis
• Clean-up damaged, dead tissue
• Role in ‘pruning’ of synapses in normal development

Neurons

What makes neurons “special”

• Long-lived (most generated b/w 3-25 weeks gestational age)
• Extended branching (dendrites and axons)
• Electrically excitable
• Connect to small #s of other cells via synapses
• Release neurotransmitters

Macrostructure

• Dendrites
• Soma
• Axons
• Terminal buttons (boutons)

Dendrites

• Majority of input to neuron
• Passive (do not generate current flows) vs. active (generate current flows like axons)

Dendritic Spines

• Concentrate effects of local current flows, biochemical reactions

Soma (cell body)

• Varied shapes
• Nucleus
  • Chromosomes
• Organelles
  • Mitochondria
  • Smooth and Rough Endoplasmic reticulum (ER)

Axons

Axon hillock

• Transitional zone between soma and axon

Initial segment

• Action potential generated

Nodes of Ranvier

• Gaps in myelin sheath
• Neuronal membrane exposed to extracellular space
• Action potential regenerates

Axon terminals

Synaptic bouton (terminal button)

• Synapse (~5-10K per neuron)
• Pre- (sending side) and postsynaptic (receiving side) membranes
• Synaptic cleft
• Synaptic vesicles
  • Store/release neurotransmitters
• Autoreceptors & transporters

Classifying neurons

• Functional role
  • Input (sensory), output (motor/secretory), interneurons
• Anatomy
  • Unipolar
  • Bipolar
  • Multipolar

• By specific anatomy
  • Pyramidal cells
  • Stellate cells
  • Purkinje cells
  • Granule cells

Pyramidal cell (Wikipedia)

Pyramidal cell (left) | Stellate cell (right)

Morphology, physiology, gene transcription

Zeng & Sanes, 2017

Zeng & Sanes, 2017

(Boldog et al., 2018)

Neurophysiology

Why animals need brains

Sterling & Laughlin, 2015

• Escherichia Coli (E. Coli)
  • Tiny, single-celled bacterium
  • Feeds on glucose
  • Chemo (“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

• 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
    • Signal across cell within ms

C Elegans swimming.

• Caenorhabditis Elegans (C. Elegans)
  • ~10x larger than paramecium
  • 302 neurons + 56 glial cells (out of 959)
  • Swim, forage, mate

Neural communication types

• Electrical
  • Fast(er)
  • Within neurons
• Chemical
  • Diffusion slow(er)
  • Within & between neurons
  • or other cells

Electrical communication

• Electrical potential (== voltage)
  • Think of potential energy
  • Voltage ~ pressure
  • Energy that will be released if something changes

Basic principles

\[E = IR\]

• Current flow (\(I\)) across membrane
• Membrane varies in resistance (\(R\)) or permeability (\(1/R\)) to ion flow
• Product \(IR\) is electrical voltage \(E\)

• Membrane stores (& releases) charge like capacitor

Resting potential

• Measurement
  • Electrode on inside
  • Electrode on outside (reference)
  • Inside - Outside = potential

• Neuron (and other cells) have potential energy
  • Inside is -60-70 mV, with respect to outside
  • ~1/20th typical \(1.5V\) AAA battery
• Like charges repel, opposites attract, so
  • Positively charged particles pulled in
  • Negatively charged particles pushed out

Contributors to

• Ions
  • Potassium, \(K^+\)
  • Sodium, \(Na^+\)
  • Chloride, \(Cl^-\)
  • Calcium, \(Ca^{++}\)
  • Organic anions, \(A^-\)
• Ion channels
• Separation between charges
• A balance of forces

Party metaphor

• Annie (\(A^-\)) was having a party.
  • Used to date Nate (\(Na^+\)), but now sees Karl (\(K^+\))
• Hired bouncers called
  • “The Channels”
  • Let Karl and friends in or out, keep Nate out
• Annie’s friends (\(A^-\)) and Karl’s (\(K^+\)) mostly inside
• Nate and friends (\(Na^+\)) mostly outside
• Claude/Claudia (\(Cl^-\)) tagging along

Ion channels

• Macromolecules that form openings in membrane
• Different types of subunits

• Selective
• Vary in permeability
• Types
  • Passive/leak
  • Voltage-gated
  • Ligand-gated (chemically-gated)
  • Transporters

http://www.zoology.ubc.ca/~gardner/F21-08.GIF

Conditions

Neuron at rest permeable to \(K^+\)

• Passive \(K^+\) channels open
• \(K^+\) flows out
• \(K^+\) outflow creates charge separation from A-
• Charge separation creates voltage
• Voltage prevents \(K^+\) concentration from equalizing b/w inside and out

• Force of diffusion
  • \(K^+\) moves from high concentration (~140 mM inside) to low (~4 mM outside)
  • Movement of charged particles == current
• Electrostatic pressure
  • Voltage build-up stops \(K^+\) outflow
  • Voltage called “reversal potential”
  • \(K^+\) positive, so reversal potential negative (w/ respect to outside)
  • Reversal potential close to resting potential

Equilibrium potential and the Nernst equation

Neuron at resting potential has low \(Na^+\) permeability

• \(Na^+\) concentrated outside neuron (~145 mM) vs. inside (~12 mM)

• Equilibrium potential is positive (with respect to outside)

• Some \(Na^+\) flows in

• Calculate net effects of ion flow across membrane via

• Goldman-Hodgkin-Katz equation

Ions contributing to the resting potential

Summary of forces

Ion	Concentration gradient	Electrostatic force
\(K^+\)	Inside >> Outside, outward	- (pulls \(K^+\) in)
\(Na^+\)	Outside >> Inside, inward	- (pulls \(Na^+\) in)

• “Driving Force” on a given ion depends on its equilibrium potential AND current membrane potential.
• Driving force >> if membrane potential far from equilibrium potential for ion.
• Equilibrium potential
  • Voltage that keeps current (inside/outside) concentrations the same
  • Voltage membrane potential will approach if only that ion flows

Equilibrium potentials

Under typical conditions

Ion	[inside]	[outside]	Voltage
\(K^+\)	~150 mM	~4 mM	~ -90 mV
\(Na^+\)	~10 mM	~140 mM	~ +55-60 mV
\(Cl-\)	~10 mM	~110 mM	- 65-80 mV

Action potential

• Rapid rise, fall of membrane potential
• Threshold of excitation
• Increase (rising phase/depolarization)
• Peak
  • at positive voltage
• Decline (falling phase/repolarization)
• Return to resting potential (refractory period)

Components

Phase	Neuron State
Resting potential	Passive \(K^+\) allow outward flow; passive \(Na^+\) allow inward flow; \(Na^+\)/\(K^+\) moves \(K^+\) in and \(Na^+\) out
Rise to threshold	+ input makes membrane potential more +
Rising phase	Voltage-gated \(Na^+\) channels open, \(Na^+\) enters
Peak	Voltage-gated \(Na^+\) channels close and deactivate; voltage-gated \(K^+\) channels open
Falling phase	\(K^+\) exits
Refractory period	\(Na^+\)/\(K^+\) pump restores [\(Na^+\)], [\(K^+\)]; voltage-gated \(K^+\) channels close
Resting potential	Passive \(K^+\) allow outward flow; passive \(Na^+\) allow inward flow; \(Na^+\)/\(K^+\) moves \(K^+\) in and \(Na^+\) out

Neuron at rest

• Driving force on \(K^+\) weakly out
  • -70 mV - (-90 mV) = +20 mV
• Driving force on \(Na^+\) strongly in
  • -70 mV - (+55 mV) = -125 mV
• \(Na^+\)/\(K^+\) pump maintains concentrations

---

Phase	Ion	Driving force	Flow direction	Flow magnitude
Rest	\(K^+\)	20 mV	out	small
	\(Na^+\)	125 mV	in	small

Rising phase

• Voltage-gated \(Na^+\) channels open
• Membrane permeability to \(Na^+\) increases
  • \(Na^+\) inflow through passive + voltage-gated channels
  • continued \(K^+\) outflow through passive channels

---

Phase	Ion	Driving force	Flow direction	Flow magnitude
Rising	\(K^+\)	growing	out	growing
	\(Na^+\)	shrinking	in	high

Peak

• Membrane permeability to \(Na^+\) reverts to resting state
  • Voltage-gated \(Na^+\) channels close & inactivate
  • Slow inflow due to small driving force (+30 mV - 55mV = -25 mv)
• Membrane permeability to \(K^+\) increases
  • Voltage-gated \(K^+\) channels open
  • Fast outflow due to strong driving force (+30 mv - (-90 mv) = +120 mV)

---

Phase	Ion	Driving force	Flow direction	Flow magnitude
Peak	\(K^+\)	120 mV	out	high
	\(Na^+\)	20 mV	in	small

Falling phase

• \(K^+\) outflow
  • Through voltage-gated \(K^+\) and passive \(K^+\) channels
• \(Na^+\) inflow
  • Through passive channels only

---

Phase	Ion	Driving force	Flow direction	Flow magnitude
Falling	K	shrinking	out	high
	\(Na^+\)	growing	in	small

Refractory phase

Absolute

• Cannot generate action potential (AP) no matter the size of the stimulus
• Membrane potential more negative (-90 mV) than at rest (-70 mV)
• Voltage-gated \(Na^+\) channels still inactivated
  • Driving force on \(Na^+\) high (-90 mv - 55 mV = -145 mV), but too bad
• Voltage-gated \(K^+\) channels closing
  • Driving force on \(K^+\) tiny or absent
• \(Na^+\)/\(K^+\) pump restoring concentration balance

Relative

• Can generate AP with larg(er) stimulus
• Some voltage-gated \(Na^+\) ‘de-inactivate’, can open if
  • Larger input
  • Membrane potential is more negative than resting potential

Phase	Ion	Driving force	Flow direction	Flow magnitude
Refractory	K	~0 mV	out	small
	\(Na^+\)	145 mV	in	small

APs and Information Processing

• AP amplitudes don’t vary (much)
  • All or none
  • \(V_{K}\) and \(V_{Na}\) don’t vary much b/c \(Na^+\)/\(K^+\) pump always working
• AP frequency and timing vary
  • Rate vs. timing codes
  • Same rates, but different timing
  • “Grandmother” cells and single spikes

(Eyherabide et al., 2009)

Generating action potentials

• Axon hillock
  • Portion of soma adjacent to axon
  • Integrates/sums input to soma
• Axon initial segment
  • Umyelinated portion of axon adjacent to soma
  • Voltage-gated \(Na^+\) and \(K^+\) channels exposed
  • If sum of input to soma > threshold, voltage-gated \(Na^+\) channels open

Wikipedia

Propagation of action potentials

• Propagation
  • move down axon, away from soma, toward axon terminals.
• Unmyelinated axon
  • Each segment “excites” the next

• Myelinated axon
  • AP “jumps” between Nodes of Ranvier –> saltatory conduction
  • Nodes of Ranvier == unmyelinated sections of axon
  • voltage-gated \(Na^+\), \(K^+\) channels exposed
  • Current flows through myelinated segments
• Why does AP flow in one direction, away from soma?
  • Soma does not have (many) voltage-gated \(Na^+\) channels.
  • Soma is not myelinated.
  • Refractory periods mean polarization only in one direction.

Conduction velocities

Hodgkin-Huxley Equations

• Measuring APs in actual neurons. https://www.youtube.com/embed/k48jXzFGMc8
• Interview with Sir Alan Hodgkin, https://www.youtube.com/embed/vSIXbfunHYg
• Simulations
  • http://alexhwilliams.info/code/pyneuron_morph.html
  • http://briansimulator.org/demo/
  • http://www.gribblelab.org/compneuro/3_Modelling_Action_Potentials.html

Chemical communication: Synaptic transmission

• Synapse permits neuron to pass electrical or chemical messages to another neuron or target cell (muscle, gland, etc.)

• Gap junctions
  • Cytosol flows through adjacent neurons
  • Bidirectional ion flow (current) between neurons

What happens when AP runs out of axon?

• Rapid change in voltage triggers neurotransmitter (NT) release
• Voltage-gated calcium Ca++ channels open
• Ca++ causes synaptic vesicles to bind with presynaptic membrane, merge
• NTs diffuse across synaptic cleft
• NTs bind with receptors on postsynaptic membrane
• NTs unbind, are inactivated

Receptor/channel types

Leak/passive

• Vary in selectivity, permeability

Transporters/exchangers

• Ionic
  • \(Na^+\)/\(K^+\)
• Chemical
  • e.g., Dopamine transporter (DAT)

Ionotropic receptors (receptor + ion channel)

• Ligand-gated
• Open/close channel

Metabotropic receptors (receptor only)

• Triggers 2nd messengers
• G-proteins
• Open/close adjacent channels, change metabolism

Receptors generate postsynaptic potentials (PSPs)

• Small voltage changes
• Amplitude scales with # of receptors activated
• Excitatory PSPs (EPSPs)
  • Depolarize neuron (make more +)
• Inhibitory (IPSPs)
  • Hyperpolarize neuron (make more -)

NTs inactivated

• Buffering
  • e.g., glutamate into astrocytes
• Reuptake via transporters
  • e.g., serotonin via serotonin transporter (SERT)
• Enzymatic degradation
  • e.g., acetylcholine esterase (AChE) degrades acetylcholine (ACh)

---

References

Azevedo, F. A., Carvalho, L. R., Grinberg, L. T., Farfel, J. M., Ferretti, R. E., Leite, R. E., … others. (2009). Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. Journal of Comparative Neurology, 513(5), 532–541. https://doi.org/10.1002/cne.21974

Boldog, E., Bakken, T. E., Hodge, R. D., Novotny, M., Aevermann, B. D., Baka, J., … Tamás, G. (2018). Transcriptomic and morphophysiological evidence for a specialized human cortical GABAergic cell type. Nature Neuroscience, 21(9), 1185–1195. https://doi.org/10.1038/s41593-018-0205-2

Chung, W.-S., Welsh, C. A., Barres, B. A., & Stevens, B. (2015). Do glia drive synaptic and cognitive impairment in disease? Nature Neuroscience, 18(11), 1539–1545. https://doi.org/10.1038/nn.4142

Eyherabide, H. G., Rokem, A., Herz, A. V. M., Samengo, I., Eyherabide, H. G., Rokem, A., … Samengo, I. (2009). Bursts generate a non-reducible spike-pattern code. Frontiers in Neuroscience, 3, 1. https://doi.org/10.3389/neuro.01.002.2009