Memory storage 06/05 Flashcards
In order to acquire a long term memory from an experience, which overall steps must occur?
- The learning event.
- Memory encoding and formation (giving rise to STM)
- Consolidation (giving rise to LTM)
- Storage/maintainence mechanism, allowing the LTM to be maintained indefinitely.
What is a major theoretical obstacle for storage of memories that last a lifetime?
Molecules within the body are constantly turned over i.e., degraded and replaced with new ones. A lifetime storage mechanism must therefore allow replacement of molecules without disruption of the memory.
What is the CAMKII memory storage hypothesis?
John Lisman proposed a theory in 1988 that memory storage could be carried out by an autophosphorylative kinase in the synapses. These autophosphorylative molecules would allow memory storage through a positive feedback system, where denovo molecules would be incorporated into the complex and phosphorylated, as the old ones degraded. Shortly after this, CAMKII was discovered - a molecule with a high concetration in dendritic spines and with the structural potential to carry out such activity.
Several pieces of evidence (4 examples) have supported CAMKII to have a general role in memory such as:
- CAMKII antogonism with tatCN21 blocks formation of contextual fear shock memory but not maintaince
- transiently upregulated during LTP
- it interacts with gluN2b subunit of NMDA (highly calcium permeable therefore important for plasticity)
- tatCN21 (blocks binding of CAMKII to NMDA) given shortly after LTP induction abolishes LTP. NMDA-CAMKII formation was believed to capture proteins involved in synapse stabilisation (spines get bigger every time they are reactivated)
What experiment shows that CAMKII is involved in memory storage?
Spatial avoidance paradigm (lasts longer that MWM memory) was used. Control animals learn to avoid the space on the moving wheel where they recieved shocks during training and after 16 days this memory is maintained.
The reodent was administered a viral injection to transfect the genome with a form of CAMKII that cannot be autophosphorylated. This null CAMKII is incorporated into CAMKII complexes, but cannot be phosphorylated. This results in the abolishment of the fear memory by day 16.
This supports the hypothesis of both turn over and of CAMKII as storage memory, as it suggests that the denovo mutated CAMKII is incorporated into the complexes involved in memory maintainence, and that the autophosphorylation is crucial for the memory to continue being stored.
What is PKMzeta and how is it regulated?
It is a kinase within synapses that has been proposed to be a memorase molecule.
It is constutively transcribed because it does not have a regulatory domain. It’s mRNA stored in dendritic spines (as is the case with many proteins, as the nucleus is far away and does not allow for rapid changes to the proteome)
However, it is constitutively translationally repressed.
Stimulation of NMDA and Ca++ influx activates a host of kinases, which release the translational block on PKMzeta.
PKMzeta is then translated, and goes on to further stimulate its own production (positive feedback mechanism).
PKMzeta phosphorylates substates which are important in AMPAR cell surface trafficking.
What is the evidence that PKMzeta is the memory storage molecule?
It was shown in mice that ZIP (a PKMzeta inhibitory molecule) reverses LTP when given 2hrs after induction and causes loss of fear memory 24 hours after training in the spatial avoidance paradigm.
Many more experiments in rats went onto show that it had the same affect in a variety of paradigms with a wide range of delay times after memory acquisition (1 day -3 months)
What is the evidence that PKMzeta is not the memory storage molecule?
ZIP was the experimental antagonist used in all of the PKMzeta studies.
It was then shown not be specific to PKMzeta. The first set of experiments showed that LTP was not impaired in PKMzeta KO mice. Secondly, it showed that ZIP could impair LTP in PKMzeta KO mice, suggesting it is not acting to impair LTP via PKMzeta.
These results were confirmed in behavioural memory studies.
It was later shown that there is a compensatory moleculate called PKMι/λ (iota-lambda) was being upregulated in the instance of PKMzeta knock out, and that inhibiting PKMι/λ in PKMzeta knock out mice could destroy LTP. These results were then confirmed by behavioural studies.
What is the functional prion hypothesis of memory storage?
A physiological signal converts solube proteins into self-perpetuating ‘active’ forms, which go on to carry out functions important to memory functions.
CPEB is a protein which binds to and regulates synthesis of mRNA by increasing polyadenosine tail.
It is activated by PI3 kinase (downstream signalling molecule of neuronal activity) which converts it to conformation A (soluble, inactive) to conformation B, which goes on to carry out more conversions and to enhance the synthesis of genes important involved in synaptogenesis (genes unknown).
There is not much evidence that hippocampal memory storage is underpinned by synaptogenesis, so much as enlargement of synpases. But this mechanism may occur elsewhere.
It has been shown that CEPB3 KO after morris water maze learning (using cre-loxp exision) significantly reduces the time spent searching for the platform in the correct quadrat (i.e, rat randomly swims around, memory lost.
What is the evidence for epigenetics as the modulator of memory storage?
An experiment has shown a long term increase in DNA methylation for the calcineurin (phosphotase enzyme) in the anterior cingulate cortex after fear conditioning, which leads similarly to a decrease in mRNA and protein synthesis.
Blocking DNA methylation of this gene 29 days after fear training results in a significant reduction in freezing, suggesting that DNA methylation is required for remote Contextual fear memory. Inhibiting DNA methylation 1 day after training do not effect the fear memory. Supports the idea of systems consolidation of memory.
