Tagged for Failure- CREB, CBP and other molecules associated with memory disruption

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Short-term memory consolidation into long-term memory involves the strengthening of synapses. In the hippocampal CA3-CA1 pathway strengthening is LTP and NMDAR dependent. Declarative memory connections are formed and branch out for long-term maintenance starting at these synapses by transcription factors activated following a neural impulse. Herein, molecules that act to phosphorylate and activate other molecules, such as Cdk5[1], and that regulate gene expression, such as CREB and CBP[2] will be examined. Deletions in these molecules can cause deficits in memory consolidation through multiple mechanisms. cAMP response-element binding protein (CREB) is considered one of the most important molecules as a tag for the memory trace in declarative memory,[3] and there is significant research on the pathways involved in CREB activation, its effects in consolidation, and where errors can occur. Researching and understanding the molecular biology and chemistry of our brains is important in order to develop techniques to predict and treat neuropsychiatric and neurodegenerative disorders. Patients suffering from Alzheimer’s disease, which is characterized by learning and memory impairments, could benefit from treatments directed at reducing the molecular inhibition of memory, such as the BACE1 enzyme which inhibits the cAMP-PKA-CREB signaling pathway.[4] Another big topic in this field is selective memory erasure, and it may become extremely important in the removal of unwanted memories, for example in the treatment of post-traumatic stress disorders. Study and development of techniques to erase specific memories is a broadening area of research, and one paper by Han et al published in 2009 shows progress and potential.[5]

1. Failures of CREB

CREB: cAMP Response Element Binding Protein
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1.1. The CREB Pathway

Cyclic-AMP response element binding protein, CREB, is a transcription factor present in neurons with effects on protein synthesis important for the potentiation of synapses and the formation of long-term memory. CREB in hippocampal neurons is activated through phosphorylation at its serine 133 domain.[6] This phosphorylation can be from a variety of kinases, which are usually active and/or up-regulated following a neural impulse. Protein kinase A activated from a cAMP signaling cascade, and calcium-calmodulin kinases have been specifically implicated as phosphorylators of CREB.[6] Mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) are important in phosphorylating CREB as well, and their inhibition caused failure in novel object recognition memory in mice.[7] For the Schaffer Collateral pathway (CA3-CA1), this process is dependent on signaling through the opening of N-methyl-D-aspartate (NMDA) receptors.[6] Once activated, CREB regulates the transcription of target genes important for LTP by binding to cAMP responsive element (CRE) promoter domains.[6] These target genes are involved with the strengthening of the synapse and can include scaffolding proteins such as PSD-95.[4] Co-activation of CREB for gene transcription can also occur through the binding of it to CREB binding protein (CBP).[2]

Molecular Pathways for CREB Phosphorylation
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Any molecular error or manipulation which can interrupt this pathway can be damaging to memory because of the importance this activation and effects of CREB play in the consolidation of short-term memory into the long-term. Administration of antisense CREB oligodeoxynucleotides into the CA3 region of the hippocampus reduced the levels of phosphorylated CREB (pCREB) in that region.[8] To examine the effects on learning and spatial memory, the researchers used a Morris water maze behavioural test.[8] Compared to a control sense oligodeoxynucleotide group, the mice with lower levels of pCREB performed the same in the short-term memory probe test, but when tested 24 hours later they did not retain their training.[8] They had overall lower recorded levels of memory retention based on less annulus crossings over the target region, and less time spent in the appropriate quadrant.[8] Lower levels of pCREB in the CA3 region therefore diminished long-term memory.[8] This is showing that the consolidation of memories from short-term into long-term is a CREB dependent process. Without the phosphorylation of CREB and the subsequent gene transcription and protein synthesis, long-term memory formation and behavioural output are negatively affected.

Deficiency in the CREB alpha and delta isoforms has been proven to disrupt the consolidation of memory and the environmental performance on memory tests.[9] An important approach to this is to examine not just disruption in memory retention, but the effects early failure has in subsequent trials as well. Hebda-Bauer et al subjected mice with CREBαδ genetic deficiency to two variations of the Morris water maze test.[9] The MWM4 variation provided an easier learning environment with four training trials per day, and the MWM2 variation was more difficult, having two trials per day.[9] The CREBαδ deficient mice performed significantly better in the MWM4 test.[9] The experimenters then compared the performance of CREBαδ deficient mice that underwent the MWM4 test and then the MWM2 to those that did the trials in the opposite order.[9] When these mice were presented with the more challenging MWM2 trial first with no prior training, they performed worse on the MWM4 follow-up trial than without any previous training.[9] These results indicate an important relationship between the molecular basis of long-term memory and environmental performance. Given the existent genetic disadvantage to a CREBαδ deficiency, failure in training trials such as in the MWM2 test can lead to more failure in later tests, further increasing the memory deficits.[9] On the other hand, when the MWM4 test was run before the MWM2, performance in the MWM2 was better.[9] Therefore the effect of molecular disruptions on memory is largely dependent on environmental conditions, in which subjects with previous failure have more difficulty succeeding in the future. Applying this concept to human disease, someone who has been affected by Alzheimer’s, in which there is a complex molecular deficit in memory,[4] could benefit from a stronger understanding of the interaction between molecular and environmental memory failure.

1.2. CREB in Alzheimer's Disease

Alzheimer’s disease is a neurodegenerative disorder characterized by a loss of memory, particularly in consolidation and retrieval.[4] There is degradation of the neurons and structure of the brain usually beginning from the medialtemporal lobe which contains the hippocampus.[4] β-amyloid plaques, which build up in brains affected by Alzheimer’s disease, have an inactivating effect on the pathway responsible for phosphorylating CREB.[4] Through both the degeneration of the brain structure and the β-amyloid plaques, memory formation and storage is damaged in patients with Alzheimer’s. The change in enzymatic activity may act to negatively affect memory as well through disrupting the phosphorylation of CREB and in so consolidation.[4] Amyloid precursor protein is cleaved to form β-amyloid in Alzheimer’s disease by an enzyme complex containing γ-secretase and β-secretase (BACE1) parts.[4] An increase in the levels of BACE1 occurs in Alzheimer’s affected brains, and was shown to decrease the levels of pCREB in the brains of BACE1 transgenic mice.[4] The activity of PKA, and the levels of PSD-95 and cAMP were decreased as well.[4]

BACE1’s effect on the phosphorylation of CREB and memory consolidation is independent of the negative regulation of the CREB pathway by β-amyloid. Mice cells with an amyloid precursor protein knockout and that overexpressed human BACE1 had a similar decrease in pCREB as cells without the knockout.[4] Adenylate cyclase is a membrane bound protein that catalyzes the conversion of ATP into cAMP.[4] The transmembrane domain of BACE1 interacts with adenylate cyclase.[4] This interaction is likely the process by which an increase in BACE1 can decrease PKA activity and the levels of pCREB. This is another explanation for the phenotypic memory failure in Alzheimer’s disease. It exemplifies another pathway involved in disruptions in consolidation, and it explains why memory failure becomes so complex in this neurodegenerative disease.

1.3. Cdk5

Cyclin-dependent kinase 5 (Cdk5) plays a part in the regulation of a multitude of neuronal processes in the central nervous system including axonal growth, synaptic plasticity, and neurotransmission.[10] Although the exact pathway is unknown, Cdk5 has been shown to be implicated in hippocampal memory formation.[1] Cdk5 loss of function generated by Cre T29-2 insertion into the CA1 cells of mice caused a decrease in associative and spatial memory formation.[1] Performance in the Morris water maze test and in a context-dependent fear memory test was impaired.[1] A likely mechanism by which a Cdk5 knockout causes failures in memory is through the phosphorylation of CREB. Immunohistochemistry on Cdk5f/f/T29 (Cdk5 loss of function) mice neurons showed reduced pCREB in the CA1 but not in surrounding tissues.[1] Further research is required to determine the exact interactions in this disruption of memory, but ablation of Cdk5 in the CA1 of the hippocampus has significant effects in the encoding of memory through regulation of the CREB pathway.[1]

2. Failures of CBP

CBP: CREB Binding Protein
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2.1. CBP Knockout

CREB-binding protein (CBP) is a gene transcription co-activator which in the presence of pCREB can bind DNA and assist in gene expression.[6] It is involved in epigenetic modification of chromatin which can allow or block the transcription of the DNA through acetylation or deacetylation respectively.[11] CBP is a histone acetyl transferase (HAT) protein that acetylates chromatin when it is bound to pCREB.[11] Via its role in gene transcription CBP is an important molecular regulator in the CREB pathway for memory consolidation and LTP. Mice CA1 hippocampal neurons without the presence of CBP show impairments in CREB mediated gene transcription, LTP, and long-term memory.[2] Barrett et al studied mice introduced with an adeno-associated virus paired with Cre recombinase in order to create a focal deletion of CBP (Cbpflox/flox).[2] Twenty-four hours after contextual fear conditioning there was significantly less freezing in Cbpflox/flox mice compared to Cbp+/+ mice, implying an impairment in memory consolidation.[2] There was a decrease in the CREB-mediated expression of c-fos as well, a gene associated with LTP and long-term memory.[2] The molecular and memory failures exhibited in Cbpflox/flox mice can be attributed to the disruption of CREB:CBP gene expression because these mice had normal levels of pCREB.[2] A loss of CBP in the CA1 of the hippocampus is another mechanism through which failure in memory consolidation can occur, even with proper functioning of the entire synaptic strengthening signaling cascade.

2.2. Rubinstein-Taybi Syndrome

Rubinstein-Taybi syndrome (RTS) is a neurodevelopmental disease associated with deficits in the normal functioning of the central nervous system.[12] Patients suffering from RTS exhibit phenotypes of mental retardation, body structural defects,[12] and some disruptions in long-term memory.[13] Mutations in CBP/p300 HAT proteins have been shown to be responsible for 55% of RTS cases.[12] p300 is an analogue to CBP that has been shown to activate similar gene sequences, but it does not make up for a lack of CBP.[2] Mice models of RTS are generated through heterozygous deletion or truncation of CBP.[12] Memory consolidation into long-term is affected in RTS mice (CBP knockout) because of the lack of HAT activity.[12] This memory disruption can be reversed with administration of inhibitors for histone deacetylases (HDAC), molecules which normally close chromatin to prevent transcription.[12] This proposes a potential treatment for human patients suffering from RTS. Epigenetic modification by HAT and HDAC regulates the expression of genes crucial for the consolidation of memory and is another mechanism through which memory failure can occur.

3. Selective Memory Erasure

Selective Memory Erasure
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Consolidation of memory from short-term into long-term is just one of a few processes of how memory is formed, stored, and recalled in the brain. Memory failure can occur at any point along the modal model of memory. In order to specifically ablate a memory there must be disruption of the memory storage, and hence cause failure in the retrieval process. This is a currently broadening field that may have clinical applications in the future to treat, for example, post-traumatic stress disorders. In 2009 Han et al using mice models, selectively erased a memory with CREB being used as a tag for the memory trace.[5] Specificity was insured by using a Cre-recombinase method to introduce a virus into the lateral amygdala of mice.[5] It encoded for diphtheria toxin receptors and high levels of CREB, and a control group was also created with just the receptors.[5] When injected with the toxin, only neurons encoding the diphtheria toxin receptors would be ablated because the receptors do not normally occur in the mice genome.[5] A contextual fear memory in which a foot shock was associated with a tone was trained and the neurons expressing the higher levels of CREB were recruited into the memory.[5] Following apoptosis of the high-CREB lateral amygdala neurons, freezing to the sound of the tone resembled that of the pre-training baseline.[5] Although approximately the same number of neurons were ablated in the control group, memory retrieval was not affected.[5] This is because the damage to the lateral amygdala was broad instead of being concentrated on the fear memory.[5]

As declarative memory is stored for the long-term, cortical neuronal connections become recruited and strengthened.[14] The pathways where the memory was originally formed, such as in the hippocampus or the amygdala are less implicated in its storage.[14] It is believed that when memory retrieval occurs the original pathway is first activated, which then sends outgoing impulses to the strengthened cortical storage of the memory.[14] Two key points arise from this. Firstly, although when a memory is stored for the long-term it becomes nearly independent of the original pathways which formed it, these connections are still required for retrieval. Secondly, these neural connections can be targeted and erased, no longer allowing memory retrieval from storage in cortical regions.[5]

1. Guan, J., Su, S., Gao, J., Joseph, N., Xie, Z., Zhou, Y., Durak, O., Zhang, L., Zhu, J.J., Clauser, K.R., Carr, S.A., Tsai, L. (2011). Cdk5 is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling Pathway. PLoS ONE 6(9): e25735.
2. Barrett, R.M., Malvaez, M., Kramar, E., Matheos, D.P., Arrizon, A., Cabrera, S.M., Lynch, G., Greene, R.W., Wood, M.A. (2011). Hippocampal Focal Knockout of CBP Affects Specific Histone Modifications, Long-Term Potentiation, and Long-Term Memory. Neuropsychopharmacology. Vol. 36, p. 1545-1556.
3. Kim, J., Kwon, J., Kim, H., Han, J. (2013). CREB and neuronal selection for memory trace. Frontiers in Neural Circuits. Vol 7 (44), p. 1-7.
4. Chen, Y., Huang, X., Zhang, Y., Rockenstein, E., Bu, G., Golde, T.E., Masliah, E., Xu, H. (2012). Alzheimer’s β-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of β-amyloid. J Neurosci. 32(33): 11390-11395.
5. Han, J., Kushner, S., Yiu, A., Hsiang, H., Buch, T., Waisman, A., Bontempi, B., Neve, R., Frankland, P., Josselyn, S. (2009). Selective Erasure of a Fear Memory. Science. Vol. 323, p. 1492-1496.
6. Silva, A.J., Kogan, J.H., Frankland, P.W., Kida, S. (1998). CREB and Memory. Annu. Rev. Neurosci. 21:127-148.
7. Bozon, B., Kelly, A., Josselyn, S.A., Silva, A.J., Davis, S., Laroche, S. (2003). MAPK, CREB and zif268 are all required for the consolidation of recognition memory. Phil. Trans. R. Soc. Lond. B 358, 805-814.
8. Florian, C., Mons, N., Roullet, P. (2006). CREB antisense oligodeoxynucleotide administration into the dorsal hippocampal CA3 region impairs long- but not short-term spatial memory in mice. Learning & Memory. 13:465-472.
9. Hebda-Bauer, E.K., Watson, S.J., Akil, H. (2005). Cognitive performance is highly sensitive to prior experience in mice with a learning and memory deficit: Failure leads to more failure. Learning & Memory. 12:461-471.
10. Zhu, J., Li, W., Mao, Z. (2011). Cdk5: mediator of neuronal development, death and the response to DNA damage. Mech Ageing Dev. 132(8-9): 389-394.
11. Bedford, D.C., Kasper, L.H., Fukuyama, T., Brindle, P.K. (2010). Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases. Epigenetics. 5(1): 9-15.
12. Li, J., Zhao, G., Gao, X. (2013). Development of neurodevelopmental disorders: a regulatory mechanism involving bromodomain-containing proteins. Journal of Neurodevelopmental Disorders. 5:4.
13. Alarcon, J.M., Malleret, G., Touzani, K., Vronskaya, S., Ishii, S., Kandel, E.R., Barco, A. (2004). Chromatin Acetylation, Memory, and LTP are Impaired in CBP+/- Mice: A Model for the Cognitive Deficit in Rubinstein-Taybi Syndrome and Its Amelioration. Neuron. Vol. 42, 947-959.
14. Gal-Ben-Ari, S., Kenney, J.W., Ounalla-Saad, H., Taha, E., David, O., Levitan, D., Gildish, I., Panja, D., Pai, B., Wibrand, K., Simpson, T.I., Proud, C.G., Bramham, C.R., Armstrong, J.D., Rosenblum, K. (2012). Learning & Memory. 19:410-422.
15. Tardito, D., Perez, J., Tiraboschi, E., Musazzi, L., Racagni, G., Popoli, M. (2006). Signaling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Critical Overview. Pharmacological Reviews. Vol. 58, No. 1:115-134.

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