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
Schwann Cells
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
Glial Cells - Myelination
Oligodendrocytes
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 long-term memory, forgetfulness, slowed recall
Glial Cell Dysfunction - Tumours
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.
Neuron Morphology and Structure
Typical Neuron Dendrites Cell body (soma) Axon Axon terminals
Neuron - Basic Cell Structures
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
Neuron – Signalling Specialisations
Specialised secretory cell Targeted and long distance Irritability – responds to being stimulated Collect Information Integrate Information Transmit Information
Neuron – Signalling Specialisations
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
Neuron – Signalling Specialisations 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
Neuron – Signalling Specialisations
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
Neuron – Signalling Specialisations
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 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 ???
Neuronal Communication
3 Phases
Collection and integration of information
Transmission of information along the axon
Transmission of information from the axon terminals
Membrane Potentials
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)
Neuronal Communication
Collection and integration of information
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
Neuronal Communication
Transmission of information 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
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
repolarisation
hyperpolarisation
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
Neuronal Communication
Transmission of information from the axon terminals
The Synapse
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)
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
types
Small molecules
glutamate, gaba, acetylcholine, norepinephrine
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 pre-synaptic membrane, waiting for the trigger to be released
Small Molecules - Classes
Amino acids
Monoamines
Acetylcholine (ACh)
Soluble gases
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
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
Release of Neurotransmitter
Exocytosis
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
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 ligand-activated 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 Cl- flows 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 pre-synaptic receptors
‘Destroyed’ in the gap, before they get to the post-synaptic receptors.
Taken up by post-synaptic receptors
7 steps in neurotransmitter action
- neurotransmitter molecules are synthesised from procursers 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 into the synapse
- 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
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 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 thebinding 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
Agonistic drug effects
L-Dopa increases synthesis of dopamine
black widow spider venom- increase release of ACh
Nicotine stimulates ACh receptors
Amphetamine- 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
Key Learnings
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
