Molecular Mechanisms of Long-Term Memory Storage
The primary focus of research in the Abel lab is to understand the cellular and molecular mechanisms of long-term memory storage with a focus on the mammalian hippocampus. One of the hallmarks of long-term memory storage is that it requires the synthesis of new genes and new proteins, which act to alter the strength of synaptic connections within appropriate neuronal circuits in the brain. How are the various signals acting on a neuron integrated to give rise to appropriate changes in gene expression? How are changes in gene expression maintained to sustain memories for days, months and even years? In our lab, we have focused on transcriptional co-activators such as CREB-binding protein (CBP) and p300, leading us to investigate the effects of histone acetylation and other epigenetic modifications in memory storage. Signals from synapses drive the transcriptional processes that are required for memory storage. A major challenge in the study of these synaptic signals is how the pathway specificity of synaptic plasticity is maintained in the face of diffusible second messengers, such as cyclic AMP (cAMP), and diffusible proteins, such as the catalytic subunit of protein kinase A (PKA). We are investigating the role of A-kinase anchoring proteins (AKAPs), which restrict PKA to specific subcellular locations, to define how signal transduction pathways in neurons are able to exhibit spatial specificity.
We are also investigating processes that can modulate long-term memory. For example, the biological function of sleep has remained elusive, but studies suggest that one function of sleep may be to mediate memory storage. First, sleep appears to facilitate the formation of hippocampus-dependent memories, and sleep is increased following training. Second, sleep appears to be regulated by many of the same molecular processes that contribute to memory storage, including the transcription factor cAMP response element-binding protein (CREB) and the PKA signaling pathway. By using conditional genetic approaches and gene expression studies, we are striving to elucidate the machinery underlying sleep/wake regulation and define the role of sleep in the consolidation of long-term memory. Our studies also reveal that sleep deprivation impairs memory consolidation and synaptic plasticity by impairing signaling through the cAMP pathway.
Cognitive deficits accompany many neurological, psychiatric and neurodevelopmental disorders. We are interested in determining how our knowledge of the cellular and molecular mechanisms of synaptic plasticity and memory storage can help us understand the cognitive deficits that are seen in patients with schizophrenia, autism and intellectual disability. Recent evidence suggests that disturbances in specific intracellular signaling pathways may contribute to schizophrenia. Studies in humans indicate that activity within the cAMP/PKA signaling pathway may be increased in the central nervous systems of schizophrenia patients, and our work suggests that this pathway plays a role in endophenotypes of schizophrenia in mice. With these translational approaches, we hope to identify novel targets for the development of new therapeutics to treat psychiatric and neurodevelopmental disorders.
Vecsey, C. G., Baille, G., Jaganath, D., Havekes, R., Daniels, A., Wimmer, M., Huang, T., Brown, K., Li, X.-Y., Descalzi, G., Kim, S. S., Chen, T., Shang, Y.-Z., Zhuo, M., Houslay, M. D. and Abel, T. (2009). Sleep deprivation impairs cAMP signaling in the hippocampus. Nature 461: 1122-1125.
Havekes, R. and Abel, T. (2009). Genetic dissection of neural circuits and behavior in Mus musculus. Advances in Genetics 65: 1-38.
Halassa, M. M., Florian, C., Fellin, T., Munoz, J. R., Abel, T., Haydon, P. G. and Frank, M. G. (2009). Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 61: 213-219.
Kelly, M. P., Stein, J. M., Vecsey, C. G., Favilla, C., Yang, X., Bizily, S. F., Esposito, M. F., Wand, G., Kanes, S. J. and Abel, T. (2009). Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing G alpha s, a G-protein subunit genetically linked to schizophrenia. Molecular Psychiatry 14: 398-415.
Isiegas, C., McDonough, C., Huang, T., Fabian, S., Wu, L-J., Xu, H., Zhao, M-G., Kim, J-I., Lee, Y-S., Lee, H-R., Ko, H-G., Lee, N., Son, H., Zhuo, M., Kaang, B-K. and Abel, T. (2008) A novel conditional genetic system reveals that increasing neuronal cAMP enhances memory and retrieval. Journal of Neuroscience 28: 6220-6230.
Abel, T. and Zukin, R. S. (2008). Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders. Current Opinion in Pharmacology 8: 57-64.
Nie, T. #, McDonough, C. B. #, Huang, T., # Nguyen, P. V. and Abel, T. (2007). Genetic disruption of protein kinase A anchoring reveals a role for compartmentalized kinase signaling in theta-burst long-term potentiation and spatial memory. Journal of Neuroscience 27: 10278-10288. #Co-first author
Vecsey, C. G., Hawk, J. D., Lattal, K. M., Stein, J. M., Fabian, S. A., Attner, M. A., Cabrera, S. M., McDonough, C. B., Brindle, P. K., Abel, T.# and Wood, M. A. # (2007). Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CREB-binding protein-dependent transcriptional activation. Journal of Neuroscience 27: 6128-6140. #, corresponding authors