In this post I am going to go into some details about explicit memory, In essence, the things you think of when someone says memory are the explicit ones, like what we call our actual memories and learning facts, being able to recall and learn. So if you read anything I write and remember just one thing, your brain will have made the following changes in a few synapses in the hippocampus.
This is what the hippocampus looks like, inputs enter from the cortex (usually association cortices after being consolidated with all different senses) to the dentate gyrus which signal to the CA3 neurons via mossy fibres, CA3 neurons also receive direct input from the cortex. The CA3 neurons then signal to CA1 neurons via the schaffer collateral pathway, the synapses between this pathway and CA1 neurons are also innervated by dopaminergic neurons acting as interneurons.
Hippocampal neurons release glutamate so the post synaptic membrane consists of AMPA, Kainate and NMDA receptors. AMPA and Kainate receptors are sodium selective ion channels that open in response to glutamate. The opening of these channels and sodium entering will depolarise the membrane, if this depolarisation reaches +40mV an action potential ensues. NMDA receptors are different in that, when glutamate binds (along with glycine) the NMDA receptor opens however its conductance is 0 because a magnesium ion is blocking the entry, so although open it is not contributing anything to depolarisation. Magnesium ions are positively charged so the depolarisation of the membrane repels the ion pushing it out of the NMDA channel. by the time this occurs the action potential will be over. But if the next action potential is in quick succession then the magnesium cannot re-enter in time and the NMDA receptor can allow calcium into the neuron. There is more detail on this in the first synaptic plasticity post.
The influx of calcium controls the first 2 mechanisms:
The first is the activation of Src tyrosine kinase, calmodulin dependant protein kinase II and protein kinase C which will phosphorylate readily releasable pools of vesicles filled with AMPA and Kainate receptors causing their insertion into the membrane as well as phosphorylating existing receptors which will keep them in the activated state longer. The increase in channel number means that when glutamate is released, more channels can be opened and they will be open longer, therefore the signal has been potentiated. This is immediate long term potentiation but it does not last long, only minutes.
The second is changes to translation, because the AMPA changes cannot last long so another process needs to adapt to strengthen the synapse. The main 'synaptic plasticity' post debunks a few myths and oversimplifications mRNA and ribosomes so I will not talk about it here. Protein synthesis requires initiation factors to bind to the 5' (prime) untranslated region and other proteins such as transport factors bind the 3' untranslated region of the mRNA. Ribosomes will interact with the initiation factors to regulate the rate of synthesis and will read the mRNA code to make a polypeptide. There are three important regions in the ribosome, the aminoacyl site where the tRNA binds to the mRNA, the peptidyl site is just after which is where the amino acid on the end of the next tRNA forms peptide bond with the previous amino acid in the sequence. Finally is the exit site which is where the tRNA detaches from its amino acid and the mRNA. Initiation factors control these areas b changing the shape to increase the rate at which the mRNA moves through the ribosome. The initiation factors are also interacting with their binding proteins and when interacting with binding proteins they cannot be interacting with the ribosome, so this acts as inhibition.
Calcium entry through NMDA receptors will activate the kinase, mTORC1 or protein kinase C which phosphorylate eIF4E binding protein which prevents it binding to the eIF4E initiation factor. Stopping this interaction means that the initiation factor binds to the ribosome for longer thus increasing the translation of proteins such as AMPA receptor subunits which will keep synaptic strength high until transcription increases, which is the long term change.
So this last mechanism is changes to translation, and it is largely the same as in pre-synaptic, but it is activated differently.
I mentioned earlier that the schaffer collateral pathway innervates the CA1 neurons along with dopaminergic neurons. Well when signals are coming in rapid succession (repeating something increases the chance of memory) the dopaminergic neurons release dopamine to the CA1 neurons where they bind to either D1 or D5 receptors which are Gs protein coupled receptors so they cause the increase in adenylate cyclase, leading to an increase in cAMP levels which will activate rotein kinase A by binding to the regulatory unit to release the catalytic component. The PKA then enters the nucleus and phosphorylates CREB so it can bind to CRE on the promoter region and have CBP bind, this process will cause the acetylation of histones, freeing many genes to be more rapidly transcribed. Some of these genes will add to the existing synapse, so will increase the number of mRNA for AMPA receptors etc... to keep the synapse strong, but some will form a new synapse in that area with the presynaptic membrane, this synaptic growth coupled with strengthening of the existing synapse is what makes these explicit memories long lasting, sometimes for a lifetime.
Calcium entry through NMDA receptors will activate the kinase, mTORC1 or protein kinase C which phosphorylate eIF4E binding protein which prevents it binding to the eIF4E initiation factor. Stopping this interaction means that the initiation factor binds to the ribosome for longer thus increasing the translation of proteins such as AMPA receptor subunits which will keep synaptic strength high until transcription increases, which is the long term change.
So this last mechanism is changes to translation, and it is largely the same as in pre-synaptic, but it is activated differently.
I mentioned earlier that the schaffer collateral pathway innervates the CA1 neurons along with dopaminergic neurons. Well when signals are coming in rapid succession (repeating something increases the chance of memory) the dopaminergic neurons release dopamine to the CA1 neurons where they bind to either D1 or D5 receptors which are Gs protein coupled receptors so they cause the increase in adenylate cyclase, leading to an increase in cAMP levels which will activate rotein kinase A by binding to the regulatory unit to release the catalytic component. The PKA then enters the nucleus and phosphorylates CREB so it can bind to CRE on the promoter region and have CBP bind, this process will cause the acetylation of histones, freeing many genes to be more rapidly transcribed. Some of these genes will add to the existing synapse, so will increase the number of mRNA for AMPA receptors etc... to keep the synapse strong, but some will form a new synapse in that area with the presynaptic membrane, this synaptic growth coupled with strengthening of the existing synapse is what makes these explicit memories long lasting, sometimes for a lifetime.
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