Week 3

Question 1

Glial Cells

Answer 1

Glia support neurons
Often quoted as outnumbering neurons but probably about the same
Glia = ‘glue’ – but don’t hold neurons together
Numerous types and many function
Divisions – microglia and macroglia
Microglia – brain’s immune system
Macroglia
Myelination (Schwann cells in PNS, oligodendrocytes in CNS
Structural/functional support of neurons (astrocytes)

Question 2

Glial Cells - Myelination

Schwann Cells

Answer 2

Axon myelination in the PNS
Multiple cells along a single axon
Cell turns around the axon several times wrapping it in membrane
Can guide axon regeneration after damage
Nerves can regrow

Question 3

Glial Cells - Myelination

Oligodendrocytes

Answer 3

Axon myelination in the CNS
Single cells provides several segments, often multiple axons
Cell extensions wrap around the axon
No axon regeneration after damage
No regrowth in the CNS

Question 4

Glial Cells

Astrocytes

Answer 4

Star shaped – ‘astro’
Surround neurons and contact brain’s vasculature
‘Blood-brain barrier’ (seal off capillaries)
Support – nutrition, growth factors, clear waste, physical matrix to separate neurons
Activity - modulate neural activity, maintain efficient signalling (K+ and neurotransmitter uptake), maintain axon function

Question 5

Glial Cells

Microglia

Answer 5

Brain’s immune system
Response to injury or disease – multiply, release antigens, phagocytosis
Rapidly activate to stop pathogens
Anti-inflammatory response, eg after stroke
Eliminate excess neurotransmitters

Question 6

Glial Cell Dysfunction - MS

Answer 6

Acute, inflammatory autoimmune disease
Brain, spinal cord, optic nerves
36.6 / 100,000
Female : male 2.3 : 1
Increased prevalence with increasing south latitude in Australia (7 times more in Hobart than Queensland)
No cure but treatments to manage symptoms and slow progression – immune supress, anti-inflammatories
Visual - blurred and double vision, nystagmus, ‘flashes’
Motor - weakness of muscles, slurred speech, muscle wastage, poor posture, tics
Sensory - numbness, tingling, pain
Coordination and balance
Cognitive - short- and long-term memory, forgetfulness, slowed recall

Question 7

Glial Cell Dysfunction - Tumours

Answer 7

Frontal lobe astrocytoma
Temporal lobe glioblastoma multiforme
Gliomas are most common (40-50% of all brain tumours)
Relatively fast growing, arising from any type of glial cells, hence gliomas, astrocytomas, and oligodendrogliomas.

Question 8

Neuron Morphology and Structure

Answer 8

Typical Neuron
Dendrites
Cell body (soma)
Axon
Axon terminals

Question 9

Neuron - Basic Cell Structures

Answer 9

Ribosomes (the speckles) and endoplasmic reticulum to generate proteins: neurotransmitters
Golgi complex to package neurotransmitter into vesicles
Microtubules to transport vesicles and proteins along the axon
Synaptic vesicles contain neurotransmitter for release
Mitochondria for energy

Question 10

Neuron – Signalling Specialisations

Answer 10

Specialised secretory cell
Targeted and long distance
Irritability – responds to being stimulated
Collect Information
Integrate Information
Transmit Information

Question 11

Neuron – Signalling Specialisations

Dendrites

Answer 11

Collect information from other connected neurons (synapse)
Chemical messengers (neurotransmitters) bind to receptors and cause electrical changes 
Electrical changes spread from the dendrite and into the soma
Electrical changes weaken with distance and over time

Question 12

Neuron – Signalling Specialisations
Cell body (soma)

Answer 12

Integrates information from all of the inputs (synapses)
Electrical changes from all inputs spread to the soma and add together
Critical point – the junction between the soma and the axon (axon hillock)
If electrical changes beyond the axon hillock reaches a critical value, then the neuron will fire

Question 13

Neuron – Signalling Specialisations

Axon

Answer 13

Transmits the signal away from the soma
Signal is transmitted electrically by action potential
Myelin protects the axon and promotes fast transmission of the signal
Action potentials occur at Nodes of Ranvier

Question 14

Neuron – Signalling Specialisations

Axon terminals

Answer 14

Transmits the signal to other neurons
Signal is transmitted chemically by neurotransmitters
Terminal buttons store neurotransmitter in vesicles
Action potential triggers release into the synapse

Question 15

Sensory Neuron

Answer 15

Unipolar (pseudo-unipolar)
Afferent neuron – into the CNS
Messages from receptors to the brain or spinal cord

Question 16

Motor Neuron

Answer 16

Multipolar
Efferent neuron – out of the CNS
Messages from the brain or spinal cord to the muscles /organs

Question 17

Interneuron

Answer 17

Multipolar
Relays message from sensory neuron to motor neuron in the spinal cord
Local connections in the brain

Question 18

Neuron Dysfunction - Dementia

Answer 18

Dementia is caused by neurodegeneration – the damage and death of the brain’s neurons

Australian statistics
Second leading cause of death (leading in females)
In 2018, estimated 425,416 Australians living with dementia
Age most important risk factor – 3 in 10 people over the age of 85 and almost 1 in 10 people over 65 have dementia
Other risk factors – CV health, diabetes, cholesterol, family history, head injury
Main types – Alzheimer’s disease (AD), frontotemporal dementia (FTD), vascular dementia (VD), dementia with Lewy bodies (DLB)

Question 19

Alzheimer’s Disease

Answer 19

Cerebral atrophy
External surface of the brain with widened sulci and narrowed gyri
Commences in medial temporal lobe – hippocampus and entorhinal cortex
Early memory loss and spatial navigation impairment
Later progresses to broader cortex and subcortical
Motor difficulties, impairments in executive planning and decision making
Cortical loss and thinning of gyri
Shrunken hippocampus
Enlarged ventricles
Plaques and Tangles
Abnormal protein aggregates associated – amyloid beta and tau
Aβ – extracellular plaques
Synapse toxicity ???
Tau – intracellular tangles; twisted ropes within swollen cell body
Axon toxicity ???
Maybe causative, maybe not
Latest – Herpes virus ???

Question 20

Neuronal Communication

Answer 20

3 Phases

Collection and integration of information

Transmission of information along the axon

Transmission of information from the axon terminals

Question 21

Membrane Potentials

Answer 21

Transport
Diffusion
Outside
Inside
Important Ions:
Na+
K+
Cl-
Protein-
Resting Potential
-70mV

“POLARISED”
Local change
Less polarisation (closer to zero) 
“DEPOLARISED”
Spreads (decremental)
Decays (time)
Local change
More polarisation (away from zero) 
“HYPERPOLARISED”
Spreads (decremental)
Decays (time)

Question 22

Neuronal Communication

Collection and integration of information

Answer 22

Local polarisation change at the dendrites (and soma)

Depolarisation – excitatory post-synaptic potential

Hyperpolarisation – inhibitory post-synaptic potential

Neurotransmitter binds and an associated ion channel opens or closes, causing a Post-Synaptic Potential (PSP)

EPSP – inside gets more positive (usually Na+ flows in)

IPSP – inside gets more negative (either K+ flows out or Cl- flows in)

Fast acting

AXON HILLOCK
Effect of many local EPSPs and IPSPs spread (decremental) and decay
Axon hillock – portion of the soma adjacent to the axon
If membrane potential just beyond the hillock reaches a threshold (-55mV)
Triggers ACTION POTENTIAL

Question 23

Neuronal Communication

Transmission of information along the axon

Answer 23

Action Potential

Dendrites and soma – decremental conduction
Axon – Action Potential (AP) – active ‘firing’ of the neuron
Local depol / repol
Active so FAST
Triggered by depolarization
Key – Voltage Gated Ion Channels
Voltage Gated Ion Channels

Open and close depending on the local membrane potential

Voltage gated sodium channels – allow Na+ to rush in - Depolarisation

Voltage gated potassium channels – allow K+ to rush out – Repolarization

Question 24

Three Phases of the AP

Answer 24

rising phase
repolarisation
hyperpolarisation

Question 25

Transmission Along the Axon

Answer 25

AP is non-decremental – it does NOT decay or diminish Travels down the axon rather than passive spreading Regenerate so travel for long distances without signal loss

Question 26

Saltatory Conduction

Answer 26

Passive conduction (fast and decremental) along each myelin segment to next node of Ranvier New action potential generated at each node Fast conduction along myelin segments results in faster conduction than in unmyelinated axons Conduction in Myelinated Axons: Saltatory Conduction

Question 27

Neuronal Communication Transmission of information from the axon terminals The Synapse

Answer 27

``` Presynaptic terminal Vesicles containing NT Incoming AP triggers voltage gated calcium channels Ca2+ influx triggers NT release Receptors for NT re-uptake ``` Junction / cleft / gap NT ‘float’ briefly after release Post-synaptic terminal Receptors for the NTs Most common types of synapses Axodendritic (axon terminal buttons on dendrites) Axosomatic (axon terminal buttons on soma / cell body) But also Dendritic spines (axon terminal buttons on spines of dendrites) Dendrodendritic – dendrite to dendrite, and often bidirectional transmission Axo-axonic – (can mediate presynaptic facilitation and inhibition of that button on the post-synaptic neurone)

Question 28

The Synapse - Other Types

Answer 28

‘String of beads’ Non-directed Diffuse release from varicosities Neurohormones and modulatory neurotransmitters Gap Junction Electrical synapse

Question 29

Neurotransmitters

Answer 29

2 basic types of neurotransmitter molecules (and 2 types of vesicles) Small Large One neuron can produce and release two (or more) neurotransmitters >100 identified

Question 30

Neurotransmitters | types

Answer 30

Small molecules glutamate, gaba, acetylcholine, norepinephrine Large molecules Also endorphins, enkephalins, some hormones substance P

Question 31

Neurotransmitters | Small molecules

Answer 31

Synthesized in cytoplasm of the terminal button Packaged in vesicles by the Golgi complex Vesicles stored in clusters next to pre-synaptic membrane, waiting for the trigger to be released

Question 32

Small Molecules - Classes

Answer 32

Amino acids Monoamines Acetylcholine (ACh) Soluble gases

Question 33

Amino acids

Answer 33

``` Building blocks of proteins Fast-acting synapses in the CNS Glutamate –excitatory GABA – inhibitory Aspartate and glycine ```

Question 34

Monoamines

Answer 34

``` Synthesized from amino acid Diffuse effects (branched, string of beads synapses) Catecholamines (synthesized from tyrosine): dopamine, norepinephrine, epinephrine Indolamines (synthesized from tryptophan): serotonin ```

Question 35

Acetylcholine (ACh)

Answer 35

Acetyl group + choline Neuromuscular junction Autonomic NS

Question 36

Soluble gases

Answer 36

Nitric oxide, carbon monoxide | Retrograde transmission – feedback from post-synaptic to pre-synaptic

Question 37

Neurotransmitters | Large molecules

Answer 37

Neuropeptides – short proteins (3-36 amino acids) Assembled in the cell body by ER/ribosome Packaged by Golgi complex Transported to the axon terminal via microtubules Example – endorphins - “Endogenous opioids” Produce analgesia Receptors were identified before the natural ligand was

Question 38

Release of Neurotransmitter | Exocytosis

Answer 38

undocked synaptic vesicle cluster of protein molecules in membrane of synaptic vesicle docked synaptic vesicle cluster of protein in presynaptic membrane entry of calcium opens fusion pore fusion pore widens, membrane of synaptic vesicle fuses with presynaptic membrane molecules of neurotransmitter begins to leave terminal button presynaptic membrane

Question 39

Receptor Activation

Answer 39

Released neurotransmitter molecules produce signals in postsynaptic neurons by binding to receptors Receptors are specific for a given neurotransmitter Can also be different receptors for the same neurotransmitter

Question 40

Receptor Activation

Answer 40

2 Types of Receptor Ionotropic receptors Associated with ligand-activated ion channels Metabotropic receptors Associated with signal proteins and G proteins

Question 41

Ionotropic Receptors

Answer 41

Neurotransmitter binds and an associated ion channel opens or closes, causing a Post-Synaptic Potential (PSP) EPSP – inside gets more positive (usually Na+ flows in) IPSP – inside gets more negative (either K+ flows out or Cl- flows in) Fast acting

Question 42

Metabotropic Receptors

Answer 42

G-protein coupled Effects slower, longer-lasting, more diffuse, and more varied Neurotransmitter binds. G protein subunit breaks away. Ion channel opened/closed OR a 2nd messenger is synthesized. 2nd messengers may have a wide variety of effects

Question 43

NT Inactivation

Answer 43

As long as the neurotransmitter is in the synapse, it is active – activity must somehow be turned off Reuptake, Enzymatic Degradation, and Recycling NT can be taken up by pre-synaptic receptors ‘Destroyed’ in the gap, before they get to the post-synaptic receptors. Taken up by post-synaptic receptors

Question 44

7 steps in neurotransmitter action

Answer 44

1. neurotransmitter molecules are synthesised from procursers under the influence of enzymes 2. neurotransmitter molecules are stored in vesicles 3. neurotransmitter molecules that leak from their vesicles are destroyed by enzymes 4. action potentials cause vesicles to fuse with the presynaptic membrane and release their neurotransmitter molecules into the synapse 5. released neurotransmitter molecules bind with autoreceptors and inhibit subsequent neurotransmitter release 6. released neurotransmitter molecules bind to postsynaptic receptors 7. released neurotransmitter molecules are deactivated by either reuptake or enzymatic degradation

Question 45

Neuropharmacology

Answer 45

A drug may act to alter neurotransmitter activity at any point in its “life cycle” ``` While still in the neuron (pre-synaptically) Influence production Influence release At the synapse ‘ junction’ Influence destruction Influence up-take Influence re-uptake Agonists – facilitate/enhance Antagonists - inhibit Agonists – facilitate/enhance ``` ``` Cocaine - catecholamine agonist blocks reuptake (DAT) preventing the activity of the neurotransmitter from being “turned off” ``` Benzodiazepines - GABA agonists binds to the GABA molecule and increases the binding of GABA Physostigmine - ACh agonist inhibits acetylcholinesterase, which breaks down ACh Antagonists - inhibit Atropine – ACh antagonist Binds and blocks ACh muscarinic receptors Many of these metabotropic receptors are in the brain High doses disrupt memory Curare – ACh antagonist Bind and blocks ACh nicotinic receptors, the ionotropic receptors at the neuromuscular junction Causes paralysis Treated with physostigmine

Question 46

Agonistic drug effects

Answer 46

L-Dopa increases synthesis of dopamine black widow spider venom- increase release of ACh Nicotine stimulates ACh receptors Amphetamine- block reuptake of dopamine

Question 47

Antagonistic drug effects

Answer 47

PCPA inhibits the synthesis of serotonin Reserpine prevents storage of monoamines in vesicles Botulinum toxin blocks release of ACh Apomorphine stimulates dopamine autoreceptors; inhibits release of dopamine Curare blocks postsynaptic ACh receptors

Question 48

Communication Dysfunction

Answer 48

Myasthenia Gravis Autoimmune disease (20 per 100,000 US) Action potentials in nerves are normal Arises from a problem with synapses on muscles Immune system destroys acetylcholine (ACh) receptors at neuromuscular junction Symptoms Extreme fatigability Fluctuating muscle weakness (proximal>distal) Problems chewing (dysphagia) and talking (dysarthria) Respiratory weakness Treated with acetyl-cholinesterase (AChE) inhibitors – these increase and prolong the effects of ACh on the postsynaptic membrane Physostigmine – de-activates acetylcholinesterase (AChE) = Ach agonist Also treated with immunosuppressive drugs, or by removal of thymus gland

Question 49

Key Learnings

Answer 49

Glia – more than just structure – myelination, immunity, structural support, functional support, modulate neural activity Glial dysfunction – tumours and MS Neurons – specialised secretory cells - signalling – collect and integrate info and transmit it Neuronal dysfunction – dementia (AD) Neuronal communication – membrane potentials – resting potentials, EPSPs, IPSPs, APs Synapse – pre-synaptic, cleft, post-synaptic, some different types Neurotransmitter – small and large, different classes, excitatory/inhibitory, fast acting/diffuse, synthesis, release, receptors Neuropharmacology – agonists and antagonists Communication dysfunction - MG