Area of Research

Biophysics/Ion Channels, Synapses & Circuits

Specialization

Function of voltage-gated ion channels in dendritic integration of synaptic signals during learning and memory. Regulation of channel trafficking and function in neuronal dendrites. Genetic approaches to the study of information processing through circuit

RESEARCH THEME

We use electrophysiological recordings from brain slices, two-photon light microscopic imaging, and molecular/genetic approaches to study the mechanisms by which neuronal dendrites actively process synaptic signals to regulate information flow through neuronal circuits. One area of interest concerns the role of the HCN1 hyperpolarization-activated cation channels in regulating dendritic integration in hippocampal CA1 pyramidal neurons. Surprisingly, HCN1 knockout mice show an enhancement in hippocampal-dependent spatial learning and memory. This is associated with an enhancement of dendritic integration and in long-term potentiation of those excitatory inputs targeted to the distal tips of the dendrites, the site of greatest HCN1 expression. Now we are examining how these distal synapses contribute to learning and memory. We found that these inputs may act as training signals, inducing a novel form of synaptic plasticity at synapses that terminate on more proximal regions of the dendritic tree. We are exploring the molecular basis of this form of plasticity and designing experiments to assess its role in learning and memory.

In other experiments, we examine the molecular mechanisms that regulate the trafficking of HCN1 channels to the membrane and target the channels to their proper dendritic localization. Studies from other groups have suggested that HCN1 channel expression can be upregulated or downregulated by different patterns of neural activity, and that such changes may contribute to the development of epilepsy following an initial seizure. We previously identified a brain-specific protein, TRIP8b, that binds to the C-terminus of HCN1 and regulates its trafficking. Recent experiments show that there are at least 10 splice isoforms of TRIP8b that differentially regulate HCN1 expression. We are now examining the role of TRIP8b isoforms as regulators of neuronal activity and learning and memory.

SELECTED PUBLICATIONS

Tsay, D., Dudman, J.T. and Siegelbaum SA. (2007).  HCN1 channels constrain synaptically evoked Ca(2+) spikes in distal dendrites of CA1 pyramidal neurons. Neuron 56:1076-1089.

Dudman, J.T., Tsay, D. and Siegelbaum, S.A. (2007). A role for synaptic inputs at distal dendrites: instructive signals for hippocampal long-term plasticity. Neuron 56, 866-879.

Zhou, L. and Siegelbaum, S.A. (2007). Gating of HCN Channels by Cyclic Nucleotides: Residue Contacts that Underlie Ligand Binding, Selectivity, and Efficacy. Structure 15, 655-670.

Santoro B, Wainger BJ, Siegelbaum SA. (2004). Regulation of HCN channel surface expression by a novel C-terminal protein-protein interaction. J Neurosci. 24, 10750-10762.

Nolan, M.F., Malleret, G., Dudman, J.T., Buhl, D.L., Santoro, B., Gibbs, E., Vronskaya, S., Buzsáki, G., Siegelbaum, S.A., Kandel, E.R. and Morozov, A. (2004). A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons. Cell 119, 719-732.