Eric Klann

Molecular mechanisms of learning and memory

Our research is focused on the molecular mechanisms involved in long-term changes in neuronal function and understanding how these mechanisms might be involved in learning and memory. Hippocampal long-term potentiation (LTP) and long-term depression (LTD) are two forms of synpatic plasticity that have been proposed to be cellular substrates for learning and memory formation in mammals. LTP is a use-dependent, long-lasting increase in synaptic efficacy, whereas LTD is a use-dependent decrease in synaptic efficacy. Under the appropriate conditions, these robust forms of plasticity can be elicited in either hippocampal slices in vitro or the intact hippocampus in vivo.

One area of emphasis in my laboratory is the investigation of the role of reactive oxygen species (ROS) such as superoxide as signaling molecules during the induction and/or expression of LTP. These studies include experiments designed to determine which ROS are necessary for LTP, how ROS are produced in the hippocampus, what types of modifications ROS induce on their target proteins, and which protein kinases and protein phosphatases are modified by ROS in the hippocampus. More recently, we have begun electrophysiological, biochemical, and behavioral studies with various knockout and transgenic mice to determine how alterations in the regulation of superoxide metabolism impact hippocampal LTP and hippocampus-dependent learning and memory. A closely related line of research concerns investigations of the aberrant role of ROS in aging-related memory decline and in mouse models of diseases of memory such as Alzheimer’s disease.

A second, area of emphasis in my laboratory is the investigation of the signal transduction pathways involved in the regulation of protein translation initation factors during LTP and LTD. These studies include experiments designed to identify the signaling cascades that link NMDA and metabotropic glutamate receptor activation to alterations in the phosphorylation of eIF2alpha, eIF4E, Mnk1, and 4E-BP during various forms of LTP and LTD and whether alterations in the phosphorylation of these factors occurs during hippocampus-dependent memory. We also have begun studies with various knockout and transgenic mice to determine how alterations in the regulation of protein translation initiation factors impact various forms of LTP and LTD, as well as hippocampus-dependent learning and memory. A closely related line of research concerns investigations of the regulation of protein translation signaling pathways in mouse models of fragile X mental retardation syndrome.

We employ a multidisciplinary experimental approach to gain a greater understanding of the molecular mechanisms necessary for maintaining long-lasting changes in synaptic strength and how these mechanisms are altered in mouse models of diseases associated with memory loss. Direct enzymatic assays, immunocytochemistry, and Western blots with phospho-specific antibodies are coupled with electrophysiological studies to determine the activity and phosphorylation state of kinases, phosphatases, and numerous phosphoproteins during LTP and LTD. Similar biochemical approaches also are conducted in conjunction with hippocampus-dependent memory tasks to determine whether molecular changes associated with either LTP or LTD also are associated with memory formation in the mouse, and whether these changes are altered in genetically-modified mice that model diseases of memory and mental retardation.

E-mail: eklann [AT] cns [DOT] nyu [DOT] edu

Representative Publications

Banko, J.L., Hou, L., Poulin, F., Sonenberg, N., and Klann, E. (2006) Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depression. J. Neurosci., 26: 2167-2173.

Hu, D., Serrano, F., Oury, T.D., and Klann, E. (2006) Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase. J. Neurosci., 26: 3933-3941.

Kishida, K.T., Hoeffer, C.A., Hu, D., Pao, M., Holland, S.M., and Klann, E. (2006) Synaptic plasticity deficits and mild memory impairments in mouse models of chronic granulomatous disease. Mol. Cell. Biol. 26: 5908-5920.

Hou, L., Antion, M.D., Hu, D., Spencer, C.M., Paylor, R.E., and Klann, E. (2006) Dynamic translational and proteasomal regulation of the fragile X mental retardation protein controls metabotropic glutamate receptor-dependent long-term depression. Neuron 51: 441-454.

Hoeffer, C.A. and Klann, E. (2007) Switching gears: translational mastery of transcription during memory formation. Neuron 54: 186-189.

Hoeffer, C.A., Sachan, N., Dey, A., Wong, H., Patterson, R.J., Shelton, J.M., Richardson, J.A., Klann, E., and Rothermel, B.A. (2007) The Down syndrome critical region protein RCAN1 regulates LTP and memory via inhibition of phosphatase signaling. J. Neurosci. 27: 13161-13172.

Antion, M.D., Merhav, M., Hoeffer, C.A., Reis, G.F., Kozma, S.C., Thomas, G. Schuman, E.M., Rosenblum, K., and Klann, E. (2008) Deletion of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity. Learn. Mem. 15: 29-38.

Huddleston, A.T., Tang, W., Takeshima, H., Hamilton, S.L., and Klann, E. (2008) Superoxide-induced potentiation in the hippocampus requires the activation of ryanodine receptor type 3 and ERK. J. Neurophysiol. 99: 1565-1571.

Antion, M.D., Hou, L., Wong, H., Hoeffer, C.A., and Klann, E. (2008) mGluR-dependent long-term depression is associated with increased phosphorylation of S6 and synthesis of EF1A, but remains expressed in S6K-deficient mice. Mol. Cell. Biol. 28: 2996-3007.

Li, M., Shin, Y.-H., Hou, L., Huang, X., Wei, Z., Klann, E., and Zhang, P. (2008) Cdh1, the adaptor protein of the anaphase promoting complex, plays an essential role in early mouse embryogenesis, in maintaining replicative lifespan, and in learning and memory. Nat. Cell Biol. 10: 1083-1089.

Hoeffer, C.A., Tang, W., Wong, H., Santillan, A., Patterson, R.J., Martinez, L.A., Tejada-Simon, M.V., Paylor, R., Hamilton, S.L., and Klann, E. (2008) Removal of FKBP12 enhances mTOR/Raptor interactions, LTP, memory, and perseverative/repetitive behavior. Neuron, in press.