Molecular mechanisms of memory and brain disorders
Director, Center for Neural Science; Professor of Neural Science
- Ph.D. 1989 Virginia Commonwealth University School of Medicine
The research in our laboratory is focused on the molecular mechanisms of translational control in the brain, how they are involved in activity-dependent, long-lasting changes in neuronal function, and whether these mechanisms play a role in complex behaviors, including cognition. We also study how dysregulated translational control contributes to altered synaptic plasticity and aberrant behavior in mouse models of fragile X syndrome, intellectual disability, autism spectrum disorder, and Alzheimer's disease. We use a number of experimental approaches, including genetic, molecular, biochemical, optical, electrophysiology, and imaging experiments to delineate the molecular signaling cascades that couple receptors to the translational apparatus during long-lasting synaptic plasticity in the hippocampus, amygdala, cortex, and striatum, and whether these types of translational control are required for memory formation, social behaviors, and behavioral flexibility. We also conduct ribosome and translation profiling to identify the mRNAs that are translated and de novo proteomics to identify the proteins that are synthesized during synaptic plasticity and memory formation, and how they are altered in disease models in neurons, brain slices, human iPSC-derived neurons, and peripheral tissues. Finally, we generate new molecular tools and mouse models to study translation in specific cell types and subcellular compartments in order to understand how translational control impacts circuit function during memory formation and how these circuits are altered in mouse models of neurodevelopmental and neurodegenerative disease.
Cell type-specific labeling of inhibitory neurons in the amygdala.
Shrestha, P., Shan, Z., Marmarcz, M. Ruiz, K.S.A., Zerihoun, A.T., Juan, C.-Y., Herrero-Vidal, P.M., Pelletier, J., Heintz, N., and Klann, E. (2020) Amygdala inhibitory neurons as loci for translational control of emotional memories. Nature 586: 407-411.
Shrestha, P., Ayata, P., Herrero-Vidal, P., Longo, F., Gastone, A., LeDoux, J.E., Heintz, N., and Klann, E. (2020) A cell type-specific drug-inducible protein synthesis inhibition in mice mouse elucidates the requirement for rapid neuronal translation in memory consolidation. Nat. Neurosci. 23: 281-292.
Ostroff, L.E., Santini, E., Sears, R., LeDoux, J.E., Lhakhang, T., Tsingos, A., Heguy, A., and Klann, E. (2019) Axon TRAP reveals learning-associated alterations in cortical axonal mRNAs in the lateral amygdala. eLife 8: e51607.
Bowling, H., Bhattacharya, A., Zhang, G., Alam, D., Lebowitz, J.Z., Aryal, S., Bohm-Levine, N., Lin, D., Singha, P., Puckett, R., Zhou, L., Sharp, K., Kirshenbaum, K., Berry-Kravis, E., Neubert, T.A., and Klann, E. (2019) Altered steady state and activity-dependent de novo protein expression in fragile X syndrome. Nat. Commun. 10: 1710.
Huynh, T., Santini, E., Mojica, E., Fink, A.E., Hall, B.S., Fetcho, R.N., Grosenick, L., Deisseroth, K., LeDoux, J.E., Liston, C., and Klann, E. (2018) Activation of a novel p70 S6 kinase 1-dependent signaling cascade in the basal nucleus of the amygdala is required for the acquisition of extinction memory. Mol. Psychiatry 23: 1394-1401.
Santini, E., Huynh, T.N., Longo, F., Koo, S.Y., Mojica, E., D’Andrea, L., Bagni, C., and Klann, E. (2017) Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice. Sci. Signal. 10: eaan0665.
Ma, T., Trinh, M.A., Wexler, A.J., Bourbon, C., Gatti, E., Pierre, P., Cavener, D.R., and Klann, E. (2013) Suppression of eIF2a kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nat. Neurosci. 16: 1299-1305.
Santini, E., Huynh, T.N., MacAskill, A.F., Carter, A.G., Pierre, P., Ruggero, D., Kaphzan, H., and Klann, E. (2013) Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 493: 411-415.
Bhattacharya, A., Kaphzan, H., Alvarez-Dieppa, A.C., Murphy, J.P., Pierre, P., and Klann, E. (2012) Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 76: 325-337.