Episode 3

In order to maintain long-term memory, it has to be consolidated in the cortex

In the short term, we strengthen synapses in hpc
*** know the hippocampal circuit
Axons (pyramidal cells) leave the hpc via the fimbria fornix
o Lesions to these, memory gets impaired.
o Part of the output from the hippocampus
Concentrating on post-synaptic inotropic receptor
Mitochondria exist presynaptically. (important to remember that but they also are post-synaptic too)
Synaptic plasticity involves modifying a neural circuit
LTP involves strengthening the synapses where as LTD is the weakening of synapses
Hypothesis: changes in the synaptic strength alters behaviour
o Strengthening is likely related to learning
LTP
o Started in the spinal cord (1973)
o Begin examining it in hippocampus
o Strengthening of the synapses in a very time dependent matter
o Typically scene in glutaminergic cells
o We think this is the way you learn things
o Its modifiable because in theory we can learn or unlearn things
o Can be strengthened in an experience dependent manner
o A stronger synapse will respond with a greater depolarization
o Most of the synapses we are talking about are the excitatory synapses, hence Glu neurons.
o Synapses are strengthened to a discrete level, dont know why
o There has to be some sort of specificity (a pairing of the input): information encoded by neurons
have to be associative
Use brain slices on hpc and electrophysiology
o CA1 neurons are the last neurons before output to cortex
o Take a stimulating electrode sits immediately on top of the axons and the same time we are
exciting pre-synaptic elements and recording post-synaptic neurons
o Using tetanic high frequency stimulation of schaffer collaterals (100Hz for a few seconds)
o Elicit a strong AP record from CA1 neurons and observe plasticity
o Some models use theta burst patterns (mimics 100Hz {100 action potential/second})
Tons of glu released onto the CA1 neurons
o Go back and give minimal stimulus on CA1 gives a huge response
o Typically we dont naturally have 100Hz by one neurons but a group of neurons can have small
burst of 100Hz but not per second, rather millisecond
o Newer models include STDP- spike timing dependent plasticity (1Hz)
Phases of LTP
o Induce plasticity by giving tetanic stimulation, let that occur, wait a few seconds and then go
back to the same cell and giving the minimal stimulus
Bigger response after the delay shows ltp has occurred.
It does decrease but then it stabilizes and is long lasting, upto 24hr
o Note: NMDA doesnt open until the membrane is depolarized
o So the responses measured is in the AMPA receptor more important for expression and
maintenance of LTP where as NMDAr is needed to cause the induction of initial action potential
o What we think is happening is that tetanic stimulation results in massive release of Glu binds
post synaptic receptor Na influx in post-synapse NMDAr opens when the Mg+ is popped
out ca influx activated CAMKII and PKC etc. upregulation of AMPA
o Pharmacological inhibition by MK-801 or APV of NMDAr during induction blocks LTP
formation
Proves that NMDAr is important in induction phase of LTP
Ca and CaMKII
o Believed that Ca is very important in the induction
o Think it binds to a Calmodulin, intracellular messanger activate CaMKII alpha auto
phosphorylation of ser, thr, tyr (especially T286)
o T286A transgenic mice generated
Kinase cannot phosphorylate A so it cant auto phosphorylate cant increase kinase
activity decline in LTP
o Conclusion: CaMKIIa is important for LTP