NEUR30002 Lecture Notes - Lecture 34: Necrosis, Neuromuscular Junction, Neurotrophic Factors
11 Aug 2018
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Lecture 34
MOLECULAR MECHANISM OF NEURAL PLASTICITY:
The Hebbian Hypothesis:
* Learning occurs when two connected neurons are active simultaneously in a way that strengthens
the synaptic connection i.e. the strength between cell A and B gets stronger – ells that fire
togethe, ie togethe
* Our understanding of associative long term potentiation and associative memory is founded on the
Hebbian hypothesis which turned out to be very accurate except for the confusion caused by the use
of the word siultaeous because it is not atually aout siultaeous fiig, it’s aout a ey
short interval which has to be within narrow windows.
Molecular basis of long term potentiation:
* Thee’s assoiatie log te potetiatio hih is ost feuet ad thee’s o associative long
term potentiation. Both of them have the final common pathway which is calcium – you need a lot
of calcium into the post synaptic dendritic spine over a period of time that is probably between 10s
o illiseods ad seods if it’s loger that that or the calcium is too high, calcium becomes toxic,
calcium is a great cause of cell death).
* The source of calcium in the associative pathway is the NMDA receptor which is the logic unit of
the brain (coincidence detector). The NMDA receptor needs two situations to be occurring at the
same time in order to activate the receptor and when the NMDA receptor is active it has an inbuilt
ion channel with a very high permeability to calcium and it lets in a flood of calcium with initiates the
long term potentiation changes, to make that synapse stronger.
* So, the NMDA receptor is both the essential strength of the brain but also its Achilles heel because
that ability to let in a lot of calcium, when things go wrong and you have over excitation of the brain
as occurs in any seizure (e.g. epilepsy) you have unregulated opening of NMDA channels, so neurons
are flooded with calcium and that causes cell death and this is called cytotoxic cell death.
* In the majority of excitatory synapses or glutamatergic synapses, the post synaptic part contains
glutamate receptors and generally contains all three major types: the AMPA type (does the ordinary
work of neurotransmission – it responds quickly to glutamate by letting in a burst of sodium and
allowing a bit of depolarisation and then it closes), the NMDA receptor and the metabotropic
glutamate receptor (G-protein coupled receptor). The AMPA receptor is present for
neurotransmission purposes, the NMDA is here for logical purposes i.e. whether to strengthen or
weaken the synaptic link and the metabotropic glutamate receptor is neuromodulatory. When
you’e got etaotropi glutaate reeptors together ith NMDA reeptors, the effet of the
metabotropic is amplification, it tends to amplify the NMDA signal.
* The NMDA receptor is highly permeable to calcium when it is in its open state. It’s ot highly
permeable to magnesium due to differences in size. What happens in the normal resting cell where
we can assume that the potential in the dendritic spine is the same as the rest of the neuron (around
-70mV), it acts to suck in magnesium into the NMDA receptor pore and the magnesium is too big so
it enters the pore and gets stuck half way and forms a plug that will remain there as long as the
dendritic spine is negatively polarised at -70mV. Once the threshold is reduced from around -70mV
to -5V, the eletial foe that’s holdig the agesiu i, eoes ot eough to keep it held
and the magnesium (magnesium has energy & it has a lot of kinetic motion) will bounce out of the
NMDA receptor. So, at -50mV approximately, when the neuron or atleast the dendritic spine can be
said to be depolarised, the pore is unplugged and it is then going to respond to glutamate binding by
opening up and becoming a calcium channel in effect (it is really a cation channel, but the calcium
permeability is much higher than the sodium permeability), so calcium enters the activated NMDA
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Lecture 34
receptor.
* So, the NMDA receptor needs glutamate to be released and it needs the dendritic spine to be
depolarised by other factors which is simultaneous inputs from nearby or even distant excitatory
inputs.
* The role of the metabotropic glutamate receptor: The metabotropic glutamate receptor is usually
linked to phospholipase C (PLC) via G protein and PLC (a membrane enzyme) cleaves a membrane
phospholipid called PIP2 and it cleaves into 2 active signalling molecules, one of which is DAG which
remains in the membrane and one of which goes into the cytosol which is IP3.
* So, diacylglycerol (DAG) remains in the membrane, but it is active. It will bind to protein kinase C
(PKC) which is cytosolic but with an activated DAG, it will be held to the membrane and activated
especially if calcium is available. So, full activation of PKC needs DAG in the presence of calcium and
calcium will be present because PLC generates a lot of IP3 and IP3 acts on the smooth ER where
there are IP3 receptors and the smooth ER is (atleast in dendrites and dendritic spines) primarily a
source of intracellular calcium stores. So, it releases more calcium. So, this is why the metabotropic
G protein has an amplification effect, eause he you’e goe NMDA eeptos lettig i a flood
of aliu fo outside, you’e also ia the etaotopi eeptos eleasig aliu fom the
intracellular stores.
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Lecture 34
* Note: dendrites and dendritic spines should have ER which we associate with being around the
nucleus, but in fact the ER extends throughout the dendritic tree. Every branch of the dendrite,
every dendritic spine has an extension or contains an extension of smooth ER and even some rough
ER hih eas that you’e got i soe dedites the aility to hae potei sythesis if you a
traffic mRNA to dendrites and this does happen.
* So, each spine has an off shoot of ER and a swelling/bud with considerable capacity to contain
calcium. So, each dendritic spine comes with its own calcium store which can be released by IP3
and these lamella (membranous folds of the ER) that occur in dendritic spines are rich with IP3
receptors. So, if glutamate binds, intracellular calcium will be released and if glutamate binds and
the cell is depolarized at the same time and the NMDA receptor is activated, then there will be a big
load of calcium will outside the cell and that calcium from outside the cell is more powerful and is
able to initiate the process of long term potentiation/LTP. The difference between this and non-
associative LTP, is that in non-associative LTP the main source of calcium is voltage-gated calcium
channels in the dendritic spine (you also still have the intracellular source of calcium) and these
channels have a lower throughput and therefore you need more vigorous stimulation to activate
them.
Effects of NMDA stimulation:
* NMDA receptors needs glutamate at the same time as depolarisation
. Caliu ety ia NMDA eeptos thee’s also sodiu ety, ut aliu peeaility is
generally 10 times higher than sodium permeability)
……..oied ith…
2. Calcium release from intracellular stores
3. Calcium entry via voltage gated calcium channels, as at all synapses
…leads to…
4. Activation of CaCam kinase II (by calcium)
5. Activation of PKA & PKC (by calcium and DAG)
* The NDMA allows entry of calcium. We also get calcium from other sources like intracellular stores
and we even get calcium from voltage activated calcium channels in dendritic spines that contain
NMDA receptors. “o oltage gated aliu haels ae ot oly peset pe syaptially ut they’e
also present post synaptically. So, calcium flows through the NMDA channel and the first thing that it
does is activate the enzyme CaCam Kinase II which is central to associative LTP. Once you get
activation of the enzyme CaCam Kinase II you then get a cascade including activation of other
kinases: PKA & PKC.
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Document Summary
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