Memory Flashcards
What is synaptogenesis?
Functional connections between nerve cells
Axonal growth ones follow cues to the target tissue and form post synaptic terminals when cells stop growing
How is synapse formation competitive?
Not all neurons will form synapses
Not all synapses will persist
Synapse formation can dictate neuronal or target survival
What is needed in order to form functional synapses?
The correct receptors need to be expressed
Synapses need to be at the correct location
The correct part of the membrane needs to differentiate into the synapse
Receptors must match the target tissue
The correct number of synapses must be made (1-10,000 per neuron)
How does synaptogenesis occur at a neuromuscular junction?
On approach the motor axon differentiates into the motor nerve terminal at the contact point
Schwann cells cap the junction
The muscle cell then forms post-synaptic apparstus
What are the morphological features of synaptic specialisation?
Small vesicles at presynaptic membrane
Narrow cleft filled with ECM between pre and post synaptic membranes
Post synaptic membrane appears thickened
What are the changes when a growth cone turns into a synapse?
Filopodia retraction Tight junction formation Membrane and extracellular glycoproteins are added Presynatpic vesicles Dense extracellular matrix Receptors accumulate in the cleft
What dictates the synaptic sites?
Where the axon hits the membrane - fine spatial control is needed
The approaching growth cone talks to its target
Site availability
Post-synaptic cells can have pre-prepared sites
What are sniffers?
Cone shapes on post-synaptic cells which have some Ach receptors - attract growth cones
Describe AchR receptor clustering in the post-synaptic membrane
Initially Ach receptors present at morderate levels on the myotube surface
Innervation causes the receptors to cluster which involves the redistribution of AchRs and localised synaptic synthesis of the receptors
What other receptors cluster at the post synaptic membrane?
Glycine, GABA and glutamate receptors
What evokes clustering?
Dennervated or destroyed muscle
NMJs form where synaptic basal lamina persists
A proteoglycan was identfied called agrin
What happens when nerve is removed from innervated muscle?
The muscle regenerates, but the nerves do not
clustering is still present
What is agrin purified from?
T california
What are the mechanisms of agrin action?
Agrin binds to muscle specific kinase because it has a high affinity
Musk signals to kinase
Raspin clusters the AchRs forming a patch of membrane with clustered Ach
Musk knockout mice are agrin insensitive
What do growth cones express?
Frizzled, FGFR2, Neurexin
What do granule cells express?
Wnt7a, FGF22, Neuroglin
What is a hebbian synapse?
Co-ordinated activity of a pre-synaptic terminal and a postsynaptic neuron strengthen the synaptic connections between them
What is synaptic refinement?
Motorneuron axon/ branch loss
Describe synaptic focusing in the visual system experiement
A radioactive label to start with can be seen all over the cortex
Later striping occurs where one of the eyes is innervated
This shows alternating inputs from the eye
This is connection focusing
Most sympathetic neurons use which neurotransmitter?
Adrenaline
Most parasympathetic neurons us which neurotransmitters?
Acetylcholine
What happens of a parasympathetic neuron from a quail is transplanted into a chick in a sympathetic area?
The transplanted parasympathetic neurons swap over to the correct neurotransmitters according to their position
How can some synapses remain silent?
There is aquisition of pre-synaptic release machinery and post synaptic NMDA receptors
However, if there is no additional input they remain silent because they lack AMPA receptors
Activity recruits AMPA receptors to the postsynaptic domain to acvtivate synaptic activity
Where can silent synapses be found in the developing mature nervous system?
In neuromuscular junctions
Activation can occur in long term potentiation in the mature hippocampus
What are the types of memory?
Declarative vs non-declarative
short vs long term
What is the active zone of a presynapse?
The site of vesicle release
Also has a higher sensitivity to calcium so it can enter the cell and cause vesicle release
List three important presynapse proteins
SNARE proteins, syntaxin and snaptobresin
What is synaptogamin?
A calcium senser which links the calcium channel and the synaptic vesicle
What are the three types of vesicles in the presynaptic membrane?
1) Readily releasable pool- fast release
2) Proximal pool - substitutes the ready releasable pool, slower release
3) The reserve or resting pool
Why is it important to have fast and slow release pools?
If a s synapse is stimulated a lot it means there is no or very little vesicles in the proximal and readily releasable pool
This is important for plasticity and depression
What are the three main types of glutamate receptor?
AMPA and NMDAR (ionotropic)
mGlut (metabotropic)
Describe the mGlu receptor
Metabotropic
Coupled to a g protein
Activates adenylate cyclase which converts ATP to cAMP
Also activates phospholipase C
What does the AMPA receptor do?
Binding of glutamate causes sodium influx and potassium efflux
What is the role of the NMDA receptor?
Causes calcium influx
What conditions must be met for the NMDA receptor to work?
The membrane needs to be depolarised
Mg needs to be removed so the channel can open
What are the advantages of using ‘simple’ systems
Large neurons are easy to patch/probe
Circuit complexity is easier to understand
They can be temperature independent
Mapping = neurons can be labelled
What are the two most simple forms of memory?
Habituation and sensitisation
Name some examples of habituation in mammals
The eye blink reflex
Habituation of repetitive non-harmful stimulus presentation eg living next to a noisy road
Habituation of visual attention
Habituation of emotional responses
What type of organism is the aplysia?
A snail
What are the roles of the gill and siphon in the aplysia?
Gill = breathing Siphon = locomotion
What happens if the siphon is touched?
Aplysia shows gill withdrawal
Continual stimuli causes the reflex to reduce
Which motor neuron is in the simple reflex of gill withdrawal?
Motor neuron L7
What are the three options for a possible habituation mechanism?
1) Sensory neurons become desensitised
2) The synapse between L7 and the muscle is desensitised
3) The synapse between neurons desensitised
What is the cellular basis of habituation?
Results from a reduced synaptic strength
What tests can show that habituation is due to a reduced synaptic strength and which synapse is weakened?
Every time you stimulate the sensory neuron they still work so the desensitisation must be downstream
Stimulating the L7 neuron still gives contraction showing the neuromusclular junction is not plastic
However, stimulating the sensory neuron many times gives the same response but the response in the L7 neuron becomes smaller
How could the gill withdrawal effect be evoked?
By tail pinch or shock
What is the role of motor neuron L29?
It synapses on to the sensory neuron and has an action on g proteins
How does L29 cause the sensory neuron to become sensitised?
GCPRs are activated, so ATP is converted to the cAMP
Pka is activated
PKa causes the inactivation of potassium channels by phosphorylation for a long period of time so depolarisation lasts a long time
What is a lymnea?
A type of snail
What experiment shows non-synaptic plasticity?
Lymnea are used and are given an attractive feeding stimulus (sucrose) and a neutral stimulus (ameyl-acetate) at the same time so animals feeding behaviour adapts to associate ameyl-acetate with sucrose
What are the roles of serotomergic cerebral giant cells (SCG)
They contact many cell types and permit feeding but not involved in the feeding beahviour directly ie they act as a gate keeper
If they fire feeding is possible
There are two of these paired
What are the components of the pathway where intrinisic moculation of feeding occurs?
CBIs -> N1, N2 and N3 (CPG in a triangle) -> motor neurons = feeding
What happens after single trial of feeding in the lymnea?
There is a long lasting depolarisation of CGC after 24 hours
The exhibit a large depolarisation by 10mV
This depolarisation lasts for weeks = CGC depolarised cells
What 2 conclusions could be drawn from the results seen in lymea experiment?
The depolarisation seen is random
CGC depolarisation is needed for long term memory
How could you demonstrate deoplarisation is necessary and sufficient for learning and what are the issues with these methods?
You could kill the neuron and then train the cells - this wont work as the feeding behaviour would be completely removed
You could prevent depolarisation by hyperpolarising the neurons - could stop spiking completely
Show fictive imaginary behavior - Record from N1 neurons, show repetitive periodic bursts when animals feed
What is a hebbian synapse?
Co-ordinated activity of a presynaptic terminal and a post-synaptic neuron strengthen the synaptic connections between them
What happens if two neurons fire at the same time?
The synapse should strengthen
How can the living hippocampus be studies outside the body?
It can be sliced into thin 50um layers and kept in an oxygenated solution at 37 degrees, it will stay alive for a few hours
Where is the main input to the hippocampus from?
Entorhinal cortex
What are the three types of neurons in the hippocampus?
Dentate gyrus
CA3 neurons - project to CA1 area
CA1 neurons
The majority of LTP mechanisms have been studied between which mechanisms?
CA3 and CA1
In the CA1 neuron what happens if the CA3 neuron is stimulated?
An EPSP is produced
What is the effect of a high frequency stimulus in the CA3 neuron?
It produces long lasting potentiation for days/weeks for a long period of time
What is meant by input specificity?
If you have a neuron that revcieves two inputs (1 and 2) and you stimulate both of them but you use a hgh frequency stimulus in 1 then LTP will be oberved in the synapse between the neuron and input 1 but not input 2
The main mechanism of LTP is thought to involve what?
A critical role of calcium
What are they two types of glutamate receptor?
AMPA
NMDA (also causes calcium influx)
What must have occurred for the NMDA receptor to be activates?
The magnesium ion in the pore must be removed
What do late aspects of LTP require?
Protein synthesis
What are the changes seen in early stage LTP?
An increase in calcium in the post-synaptic boutons
What changes are seen in late stage LTP?
Po increases, the number of synapses increases, increase in the post-synaptic response
An increase in calcium activates which kinase?
Calmodulin Kinase ii (CaMKii)
Where is CaMkii abundant?
In the pre-synaptic density, makes up 2-5% of all target protein
What are the two subunits of CaMkii?
Regulatory and Catalytic
How is the catalytic subunit of CaMkii activated?
As a result of calcium calmodulin being activated which is a secondary messenger
How is CaMkii made to stable to continue its action and what is this called?
It is phosphorylated to become stable
Autophosphorylation
What is the main problem of using inhibitors in development to look at neurons?
Inhibitors are not 100% specific
What happens to AMPA receptors in LTP?
They increase in number
In late stage LTP why is cAMP signalling important?
CREB (calcium response elements) activated
CREB1 replaces CREB2 = rise in gene expression
For this to happen CREB1 has to be phosphorylated by protein kinase A
How can you test if LTP is important for memory?
Use behavioural experiments where animals memorise something and you inhibit a molecule important in LTP eg NMDA receptors
You could overexpress a molecule as well and see of the animals memorise better
How can LTP vary? Give examples
LTP between mossy fibres and CA3 is non-NMDA mediated and is mainly presynaptic - The increase in transmitter release is calcium activated
LTP in the perforant path and the dentate gyrus does not use CaMKii
What is the morris water maze?
Mice were put in a pool with a hidden platform - repeated experiment forms LTP so mice learn where the platform is
Mutations in CaMKii, NMDA, and the cAMP pathway show learning down
What is LTD?
An actively evoked long lasting reduction in synaptic efficacy
What are the two main types of LTD?
Depotentiation - reversal of a previous potentiation
LTD de novo - no previous potentiation in the synapses
What is the general mechanism of LTD?
Often requires NMDA receptors
Requires low frequency stimulus often
Often requires calcium influx and the activation of serine/threonine phosphatates (these remove phosphates from proteins)
Often involves glutamate but can involve serotin
What are endocannabinoids?
They are released post synaptically to inhibit pre-synaptic transmitter release
In the cerebellum what happens if a climbing fibre is activated?
There is subsequent strong depolarisation of the purkinje cells
What is the main ouptut of the cerebellum?
Through purkinje cells
What are the two pathways of the cerebellum?
1) mossy fibres -> granule cells -> parallel fibres and climbing fibres (each parallel fibre synapses with the purkinje cells there once)
2) Climbing fibres which synapse with purkinje cells many times
How does long term depression occur in purkinje fibres?
Parallel fibre and climbing fibre input is paired to a single purkinje fibre to evoke LTD
EPSPs can be recorded from the purkinje cell after the PF and CF is stimulated = smaller amplitude of EPSP
What is the albus marr model?
Climbing fibres indicate a motor error so weakens the parallel fibre to purkinje cell synapse
This suggests LTD can help us learn new motor skills
What does the cerebellar LTD mechanism involve?
Metabotropic glu-R, AMPA and voltage activated calcium channels (not NMDA)
What does the parallel fibre activate?
The glutamate receptor in the purkinje cells
What does protein kinase c phosphorylate in LTD and what does it cause?
AMPA receptors - at a different site than LTP (at the GluR2 subunit)
This causes endocytosis of the AMPA receptor, reducing currents
How can LTD be prevented experimentally in the cerebellum?
By using inhibitors of endocytosis as this prevents LTD
What is the BCM theory?
Bienentock, cooper and Munro theory
Suggests synapses are active when the rest of the cell isn’t being weakened
Opposite to a Hebbian synapse
ie if the cell is not very much polarised then the synapse is weakened
What is the mechanism of LTD in the CA1 and CA3 neurons of the hippocamopus?
Recording from CA1 using patch clamps and stimulate one input with a low frequency for 20 mins = EPSPs get smaller
However, sensitivity of synapse 2 will stay the same
Shows input specificity
What is the pathway for LTP in the hippocampus?
NMDA activated -> PI3K (protein kinase) -> Akt (kinase) -> phosphorylation of Gsk3
What is the pathway for LTD in the hippocampus?
Phosphatase PPI -> dephosphorylation of Gsk3
Damage to the hippocampus is associated with what?
Anterograde amnesia
