Week 3 Flashcards
Glial Cells
• 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)
Glial Cells - Myelination
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
Glial cells - Astrocytes
• 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
Glial cells - Microglia
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
Glial Cell Dysfunction - MS
• 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
Glial Cell Dysfunction - Tumours
• 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
What makes up a typical neuron?
axon terminals, axon, cell body (soma) and dendrites
What are Ribosomes (the
speckles) and endoplasmic reticulum, and what do they do?
generate proteins:
neurotransmitters
What is the golgi complex?
package neurotransmitter
into vesicles
What are microtubules?
transport vesicles
and proteins
along the axon
What are synaptic vesicles?
contain
neurotransmitter
for release
What is mitochondria?
energy
Neuron – Signalling Specialisations
• 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
Dendrites
• 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
Cell body (soma)
• 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
Axon
• 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
Axon terminals
• 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
Sensory Neuron
Unipolar (pseudo-unipolar)
• Afferent neuron – into the CNS
• Messages from receptors to the
brain or spinal cord
Motor Neuron
Multipolar
• Efferent neuron – out of the CNS
• Messages from the brain or spinal
cord to the muscles /organs
Interneuron
Multipolar • Relays message from sensory neuron to motor neuron in the spinal cord • Local connections in the brain
Neuron Dysfunction - Dementia
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)
Alzheimer’s Disease
• 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
Membrane Potentials
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)
Collection and Integration - graph
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
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
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
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
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
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
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
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
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
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)
Presynaptic
Axon terminals
Postsynaptic
At postsynaptic terminals on dendrite
The Synapse - Other Types
‘String of beads’ • Non-directed • Diffuse release from varicosities • Neurohormones and modulatory neurotransmitters Gap Junction • Electrical synapse
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
Neurotransmitters - examples of small molecules
Glutamate, GABA, Acetylcholine, Norepinephrine
Neurotransmitters - examples of large molecules
Also endorphins,
enkephalins, some
hormones
Substance P
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.
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
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
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
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
Receptor Activation- 2 Types of Receptor
Ionotropic receptors • Associated with ligandactivated ion channels Metabotropic receptors • Associated with signal proteins and G proteins
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
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.
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
Seven Steps in Neurotransmitter action
- neurotransmitter molecules are synthesised from precursors under the influence of enzymes
- neurotransmitter molecules are stored in vesicles
- neurotransmitter molecules that leak from their vesicles are destroyed by enzymes
- Action potentials cause vesicles to fuse with the presynaptic membrane and release their neurotransmitter molecules
- released neurotransmitter molecules bind with autoreceptors and inhibit subsequent neurotransmitter release
- released neurotransmitter molecules bind to postsynaptic receptors
- released neurotransmitter molecules are deactivated by either reuptake or enzymatic degradation
At terminal button:
3 classes of “small
molecule”
neurotransmitters
Amino acids
Monoamines
Acetylcholine
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
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
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
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
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
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
At terminal button:
what are the 3 classes of “small
molecule” neurotransmitters
Amino acids
Monoamines
Acetylcholine
