Week 3 Flashcards
1
Q
Glial Cells
A
• 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)
2
Q
Glial Cells - Myelination
A
Shwann cells in the PNS Oligodendrocytes in CNS • 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 • 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
3
Q
Glial cells - Astrocytes
A
• 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
4
Q
Glial cells - Microglia
A
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
5
Q
Glial Cell Dysfunction - MS
A
• 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 longterm memory, forgetfulness, slowed recall
6
Q
Glial Cell Dysfunction - Tumours
A
• 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. eg. Frontal lobe astrocytoma, Temporal lobe glioblastoma multiforme
7
Q
What makes up a typical neuron?
A
axon terminals, axon, cell body (soma) and dendrites
8
Q
What are Ribosomes (the
speckles) and endoplasmic reticulum, and what do they do?
A
generate proteins:
neurotransmitters
9
Q
What is the golgi complex?
A
package neurotransmitter
into vesicles
10
Q
What are microtubules?
A
transport vesicles
and proteins
along the axon
11
Q
What are synaptic vesicles?
A
contain
neurotransmitter
for release
12
Q
What is mitochondria?
A
energy
13
Q
Neuron – Signalling Specialisations
A
• Specialised secretory cell
• Targeted and long distance
• Irritability – responds to being stimulated
Axon terminals + axons transmit information
cell body (soma) integrates information
dendrites collect information
14
Q
Dendrites
A
• 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
15
Q
Cell body (soma)
A
• 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
16
Q
Axon
A
• 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
17
Q
Axon terminals
A
• 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
18
Q
Sensory Neuron
A
Unipolar (pseudo-unipolar)
• Afferent neuron – into the CNS
• Messages from receptors to the
brain or spinal cord
19
Q
Motor Neuron
A
Multipolar
• Efferent neuron – out of the CNS
• Messages from the brain or spinal
cord to the muscles /organs
20
Q
Interneuron
A
Multipolar • Relays message from sensory neuron to motor neuron in the spinal cord • Local connections in the brain
21
Q
Neuron Dysfunction - Dementia
A
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)
22
Q
Alzheimer’s Disease
A
• 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 hippo campus, 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 ??? • Genetic component
23
Q
Membrane Potentials
A
Resting Potential -70mV when there are more positive ions in a certain part of the inside of the cell compared to the outside: • Local change • Less polarisation (closer to zero) • “DEPOLARISED” • Spreads (decremental) • Decays (time) when there are less positive ions in a certain part of the inside of the cellcomapred to the outside: Local change • More polarisation (away from zero) • “HYPERPOLARISED” • Spreads (decremental) • Decays (time)
24
Q
Collection and Integration - graph
A
Local polarisation change at the dendrites (and soma) • Depolarisation – excitatory postsynaptic potential; the line rises on a graph • Hyperpolarisation – inhibitory post-synaptic potential; the line dips on a graph
25
Collection and Integration - in a cell
```
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 Clflows in)
• Fast acting
• 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
```
26
Transmission Along the Axon
| 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
```
27
Transmission Along the Axon
| 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
```
28
Three Phases of the AP
Rising phase- 1ms, sodium channels open then potassium channels open. At +50mV sodium channel closes.
Repolarisation - 1.5ms when sodium channel closes until 2ms when potassium channels closes.
Hyperpolarisation- 2-4.5ms
Absolute refractory- 1-3ms period
Relative refractory- 3-4.5ms
29
Transmission Along the Axon
* 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
30
Saltatory Conduction
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
31
The Synapse is made up of/
```
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
```
32
Presynaptic terminal
```
Vesicles containing NT
• Incoming AP triggers voltage
gated calcium channels
• Ca2+ influx triggers NT release
• Receptors for NT re-uptake
```
33
Junction / cleft / gap
NT ‘float’ briefly after release
34
Post-synaptic terminal
Receptors for the NTs
35
Types of synapses
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 neuron)
36
Presynaptic
Axon terminals
37
Postsynaptic
At postsynaptic terminals on dendrite
38
The Synapse - Other Types
```
‘String of beads’
• Non-directed
• Diffuse release from
varicosities
• Neurohormones and
modulatory
neurotransmitters
Gap Junction
• Electrical synapse
```
39
Neurotransmitters
```
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
```
40
Neurotransmitters - examples of small molecules
Glutamate, GABA, Acetylcholine, Norepinephrine
41
Neurotransmitters - examples of large molecules
Also endorphins,
enkephalins, some
hormones
Substance P
42
Neurotransmitters - small molecules
```
Synthesized in
cytoplasm of the
terminal button
• Packaged in vesicles by
the Golgi complex
• Vesicles stored in
clusters next to presynaptic membrane,
waiting for the trigger to
be released.
```
43
Neurotransmitters - large molecules
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
44
Small Molecules - Classes
```
Amino acids
• Building blocks of proteins
• Fast-acting synapses in the CNS
• Glutamate –excitatory
• GABA – inhibitory
• Aspartate and glycine
Monoamines
• Synthesized from amino acid
• Diffuse effects (branched, string of beads synapses)
• Catecholamines (synthesized
from tyrosine): dopamine,
norepinephrine, epinephrine
• Indolamines (synthesized from
tryptophan): serotonin
Acetylcholine (ACh)
• Acetyl group + choline
• Neuromuscular junction
• Autonomic NS
Soluble gases
• Nitric oxide, carbon monoxide
• Retrograde transmission –
feedback from post-synaptic to
pre-synaptic
```
45
Release of Neurotransmitter
Exocytosis
- undocked synaptic vesicle
- docks onto presynaptic membrane with entry of calcium opens fusion pore
- fusion pore widens membrane and the synaptic vesicle presynaptic membrane
- molecules of the neurotransmitter begin to leave the terminal button
46
Receptor Activation
```
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
```
47
Receptor Activation- 2 Types of Receptor
```
Ionotropic receptors
• Associated with ligandactivated ion channels
Metabotropic receptors
• Associated with signal proteins
and G proteins
```
48
Ionotropic Receptors
```
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 Clflows in)
• Fast acting
```
49
Metabotropic Receptors
```
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.
```
50
NT Inactivation
```
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 presynaptic receptors
• ‘Destroyed’ in the gap, before
they get to the post-synaptic
receptors.
• Taken up by post-synaptic
receptors
```
51
Seven Steps in Neurotransmitter action
1. neurotransmitter molecules are synthesised from precursors 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
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
At terminal button:
3 classes of “small
molecule”
neurotransmitters
Amino acids
Monoamines
Acetylcholine
52
Neuropharmacology
```
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
```
53
Neuropharmacology - Agonists
facilitate/enhance
• Coca - 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
54
Neuropharmacology - 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
55
Agonistic drug effects
```
-L-dopa increases
synthesis of dopamine
-Black widow spider
venom - increases release of ACh
-Nicotine stimulates ACh receptors
-Amphetamine, cocaine,
methylphenidate - block reuptake of dopamine
```
56
Antagonistic drug effects
```
-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
```
57
Communication Dysfunction
```
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
```
58
At terminal button:
what are the 3 classes of “small
molecule” neurotransmitters
Amino acids
Monoamines
Acetylcholine
