Week 1 Flashcards
What did Hebb try to come up with?
Underlying mechanism of behaviour at the neural level
What were the key discoveries made in neuroscience prior to 1949?
- Giant squid axon
- Neurotransmitters
- Structure of neurons/synapses
- Neuron doctrine
Giant squid axon
Hodgkin and Huxley
Shape about the action potential
They recorded across the membrane
Insert electrodes inside axoplasm and measure the membrane potential
Neurotransmitters
Discovered including ACH
Concept of chemical neurotransmission
Electrical signals were relayed across synapses via release of neurotransmitters
Complexity of neurotransmitters not known
Structure of neurons/synapses
Electron microscopes were beginning to be invented
Neuron doctrine: Cajal and Golgi
Staining methods to find anatomy of neurons
Idea that neurons are distinct entities
Cajal conclusion: each neuron is like any other cell - has distinct membrane bound structure - but with lots of processes
What are the 3 postulates of Hebb’s theory
- Hebbian learning
- Cell assemblies
- Phase sequence
Hebbian learning
Connections between neurons increase in efficacy in proportion to the degree of correlation between pre- and post-synaptic activity
Idea that history of presynaptic activity can alter the future activity by causing a change in that connection between two cells
Information could be encoded in the nervous system in the form of changes in the strength of synaptic communication
Brains are made up of millions of neuron
Learning and memory don’t just involve changes at 1 synapse but multiple synapse = Hebbian synapse
Cell assemblies
Group of neurons which tend to fire together
The brain basis of mental representation (images,ideas) is group or assemblies of neurons that tend to be active at the same time
Phase sequence
Thinking is the sequential activation of sets of cell-assemblies
Henry Gustav Molaison
Feb 26 1926 - Dec 2 2008
Bicycle accident age 9
Epilepsy
1953 - William Scoville - Hartford Hospital
Scoville localised epilepsy to right and left medial temporal lobes
Had chunks of medial lobe removed
Surgery effective in reducing occurrence of seizures -however side effects
Lost ability to form new long term memories but remembered events before the surgery
Able to learn new motor skills
Types of memory proposed by what people?
Psychologist William McDougall
Philosopher Gilbert Ryle
Psychologist, Willi McDougall
Implicit memory - automatic and reflexive
Memory for skills, habit and behaviours (riding a bike)
Explicit memory - conscious remembering of the past
Memory of facts or events/ spatial memory
Philosopher Gilbert Ryle
Knowing how = memory without record
Knowing what = memory with record
Region of brain effected by the brain is the cortex, what did it effect?
Hippocampus
Hippocampus
Conversion of short term memory to long term memory
Curved structure - seahorse
MRI scan of HMs 🧠
Donated body to science - study the impact on the surgery on his brain
Loss of cortical region of hippocampus
Half of the posterior region of HM’s hippocampus was intact
Only 5cm of the medial temporal lobe had been removed
The posterior parahippocampal gyrus was mostly spared
The anterior portions of parahippocampal gyrus, most of the perirhinal and most of all of the entorhinal cortices was removed
Remaining portions H.M. Hippocampi were atrophied
The case of Clive Wearing
Contracted virus cause only cold sores but in Wearings case attacked the brain (Herpes simplex encephalitis)
Unable to store new memories
Unable to control emotions and associate memories well
Profound case of total amnesia as a result of his illness
Unable to form long lasting new memories
His memory only lasts between 7 and 30 seconds
The encephalitis’s caused damage to Clive Wearings hippocampus
Drawing of Ramon Y Cajal - neural circuitry
Produced 1922 of hippocampus section
Modified version of technique of Golgi
Technique that selectively stains just some neurons
If all stained - image would be black
The beauty - allows you to see the complete anatomy of individual neurons and also see certain pathways
Individual neurons and connections between neurons were evident in drawing
Hippocampal trisynaptic circuit
Trisynaptic loop
Relay of synaptic transmission in hippocampus
What are the 3 major cell groups of trisynaptic loop
Granule cells
CA3 pyramidal neurons
CA1 pyramidal cells
Where does the first projection of the hippocampus gyrus occur
Between entorhinal cortex and dentate gyrus
What does the entorhinal cortex transmit?
It’s signal from parahippocampal gyrus to the dentate gyrus via granule cells (perforant path)
The dentate gyrus then synapses on the pyramidal cells in CA3 via missy cells
Where does CA3 region fire?
Fires to CA1 via Schaffer collaterals
What happens when low frequency AP travels down Schaffer collaterals
Release of glutamate which binds to both AMPA and NMDA receptor
What does AMPA receptors do?
Open and allow influx of Na+ into CA1 post synaptic cell resulting in slight depolarisation event in post synaptic cell
Where does glutamate bind?
NMDA receptor but no ions pass through pore because of mg2+ blockade
What is the result of glutamate + AMPA receptor
Greater depolarisation
What does influx of Na+ cause?
Large depolarisation event in post synaptic cell which repels mg2+ blockade from NMDA receptor through electrostatic repulsion
What is the consequence of NMDA receptor + glutamate
Allow Ca2+ and Na+ to enter through the pore
What is LTP?
Strengthen connection between 2 neurons
What does influx of Ca2+ activate?
Secondary intracellullar cascade
What does increase of Ca2+ contribute to?
Two phases of LTP
What is early phase?
Ca2+ binds to its binding protein and cause insertion of new AMPA receptor onto post synaptic cell membrane at CA3-CA1 synapse
Last for a few hours and require brief increase in Ca2+ level
What is late phase?
Prolonged influx Ca2+ results in increase in transcription factors resulting in gene expression and new proteins to be synthesised
What is involved in the formation of new synapses?
Growth factors
Basis of synaptic plasticity
Brain changes as it learns
Formed between CA3-CA1 Neurons
Last 24 hours up to life time
Memory processing occurs in what other brain region?
Cerebral cortex
What is the result of continuous activation of the same pathway?
Create high frequency presynaptic AP and post synaptic activation in these oath
What does strengthening of synapse strengthen?
Memory
What is Hebbs synapse
Both presynaptic activity is needed (release of glutamate)
And postsynaptic activity(to induct potentiation)
Why are glutamate receptors of particular interest ?
glutamate is the main excitatory neurotransmitter in the human brain
Acts as an excitatory neuromuscular transmitter in insects and other Arthropods
Special type of glutamate receptor: NMDA receptor
Involved in the mechanisms of synaptic plasticity in mammalian brain
Important for learning and memory
What are types of glutamate receptors?
Ionotropic glutamate receptor
Metabotropic glutamate receptor
Ionotropic glutamate receptors
Act as ligand-gated ion channels
Mediate fast excitatory neurotransmissioj in the brain
Receptor and ion channel all in one binds the neurotransmitter (glutamate) leading to opening of channel leading to influx of ions through
Metabotropic glutamate receptor
G-protein coupled receptors that act via second messenger systems to mediate slower but often long term synaptic signalling
Act to influence ion channel activity indirectly because they lead to formAtion of second messenger systems
Bind glutamate and this links via G-protein to formation of a second messenger that influences ion channel activity
Types of Metabotropic glutamate receptors (mGluR)
Relationship between Metabotropic glutamate receptors and how that leads to activation of cannabidiol receptors in the brain
GPCR - 7 transmembrane domain topology
8 identified
What are the 8 identified of domain topology?
mGluR1 mGluR2 mGluR3 mGluR4 mGluR5 mGluR6 mGluR7 mGluR8
What is 2 types of pharmacological classification of ionotropic glutamate receptor?
- Non-NMDA
- AMPA receptor
- kainate receptor - NMDA type receptors
NMDA
Receptor type unusual in properties
Critical for mechanism and memory
What has pharmacologist discovered?
Various chemicals that will selectively activate sub-group of glutamate receptors
How can you distinguish between different types of receptors?
Doing experiment
Testing on neurons
Activate current in some cells and not others
How can you isolate nicotinic receptors from organs?
Using snake toxin
What strategy was used to determine the structure of glutamate receptor for the first time?
Molecular biological approach
What assay did they use ?
Xenopus oocytes as an expression system
How did the assay work?
Take egg of Xenopus
Isolate them
Put them into a recording chamber
Insert electrode and measure currents across membrane
If you put glutamate onto egg of Xenopus - nothing happening at all - no current
Why is Xenopus a good assay system?
It doesn’t express ionotropic glutamate receptor
What did analysis of CDNA reveal?
It encoded an 889 amino-acid protein (~100 kDA)
When expressed in Xenopus - activated by kainate
this receptor was named GluK1 (now also known as GluR5)
How many AMPA receptors are there?
4
GluR1 (GRIA1)
GluR2 (GRIA2)
GluR3 (GRIA3)
GluR4 (GRIA4)
How many kainate receptors?
5
GluR5 (GRIK1)
GluR6 (GRIK2)
GluR7 (GRIK3)
KA1 (GRIK4)
KA2 (GRIK5)
Historically, what are different names used for?
Same gene product
What are clade of receptors activated by?
Kainate
What can one infer about the phylogenetic relationship of ionotropic glutamate receptors?
There must have been an ancestral kainate receptor that gave rise to these multiple types
What is nAChR?
Ionotropic receptors
respond to chemical stimuli
Incorporate an ion channel
Heteromultimers
N-terminus located extracellularly and loops through the membrane 4 times
C terminus located extracellularly
Pentameric (5 subunits)
Glutamate receptor
N-terminus located extracellularly
Transmembrane domain
Second transmembrane domain doesn’t go through the membrane - it loops in and out again
Then there’s a second and third membrane spanning region - C terminus comes to inside
What are many membrane proteins?
Glycosylated
Oligonucleotides chain attached to them
Glycosylation only occurs on extracellularly parts of protein
How can you work out if the protein is glycosylated or not?
The weight is increased
Mass of the protein is bigger on SDS page gel
What does large extracellularly region form?
2 part structures that form a binding site for glutamate
What forms the lining of a pore?
P-loop
Where does voltage gated Na+/K+/ca2+ have a p-loop between?
5th and 6th membrane spanning region
What is the role of P-loop?
Forms a favourable environment for the entry of cations
What did low resolution of ionotropic glutamate receptor indicate?
These proteins were tetrameric (4 subunits)
How is a tetrameric structure formed?
2 subunits come together to form a diner and another 2 subunits come together to form another dimer
What is the ultimate way of determining a protein structure?
X-Ray crystallography
Cryo-EM
When was the AMPA structure determined?
2009
It has a tetrameric structure
Indicated by 4 colours
Each colour represents a subunit
What are the majority of AMPA receptors in CNS?
Heteromers
Contain GluR2
What does the presence of GluR2 render?
AMPA receptors impermeable to calcium
In the absence of GluR2?
AMPA receptors are permeable to sodium, potassium and calcium
Where are GluR2 and GluR1 predominant?
In the forebrain
Low levels of GluR3 and GluR4
At most excitatory synapses in the CNS, what does AMPA receptors mediate?
Post-synaptic depolarisation
As a consequence of net influx of sodium ions
Where are kainate receptors found?
Both pre- and post- synaptically
Have modulatory roles in synaptic transmission
Evolutionary origin of ionotropic glutamate receptors?
Share little sequence similarity with ligand-gates ion channel
Channels in the nicotinic ACH/GABA/ glycine family
Where has nicotinic ACH/GABA/glycine receptors been found?
Animals
Where has genes encoding proteins ionotropic glutamate receptors found?
Plants
What does glutamate receptors mediate?
Cell to cell communication during neurotransmission
Genes of the glutamate receptor like (GLR) family have been implicated in defence against pathogens
reproduction
Control of stomata aperture and light signal
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