F A C U L T Y P R O F I L E
SIEGELBAUM, STEVEN A., PH.D.
Molecular studies of ion channel structure and function; synaptic transmission and plasticity in the mammalian brain.
Office: NYS Psychiatric Institute | Kolb Annex, 6th Floor| Room 625
The Siegelbaum laboratory is interested in how ion channels regulate the integration of synaptic information in the dendrites of neurons in the hippocampus to control memory storage. We focus on the HCN1 hyperpolarization-activated cation channels, which are targeted to the distal dendrites of CA1 pyramidal neurons, the major output of the hippocampus. Our results show that HCN1 acts as an inhibitory constraint of dendritic integration and of learning and memory; deletion of these channels in a knockout mouse enhances long-term synaptic plasticity and facilitates learning.
How are HCN1 channels targeted to CA1 dendrites to control memory storage? We identified an auxiliary subunit of HCN1 named TRIP8b, which is expressed in the brain as ten splice variants. One isoform that upregulates HCN1 expression is localized to dendrites, where it directs channel trafficking. One isoform that downregulates HCN1 expression is present in axons, where is acts to prevent channel mislocalization. Thus, the concerted actions of two splice variants with opposing effects on HCN1 expression ensure the channel’s proper dendritic localization.
How do hippcampal neurons that normally lack HCN1 differ in their processing of synaptic information from CA1 neurons? Dendrites of CA2 neurons, near neighbors to CA1, lack high levels of HCN1. This imparts CA2 dendrites with unique properties that enable these neurons to form the nexus of a powerful disynaptic circuit, directly linking cortical input to hippocampal output. Using a novel mouse model we are now examining the role of CA2 neurons in memory storage and in neurological and psychiatric diseases.
1. George, M.S., Abbott, L.F. and Siegelbaum, S.A. (2009). Hyperpolarization-activated cation channels inhibit EPSPs by interactions with M-type K+ channels. Nature Neurosci. 12, 577-584.
2. Ahmed, M.S. and Siegelbaum, S.A. (2009). Recruitment of N-type Ca2+ channels during LTP enhances low release efficacy of hippocampal CA1 perforant path synapses. Neuron 63, 372-85.
3. Santoro, B., Piskorowski, R.A., Pian, P., Hu, L., Liu, H., Siegelbaum, S.A. (2009). TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron 62, 802-813.
4. Chevaleyre, V. and Siegelbaum, S.A. (2010). Strong CA2 pyramidal neuron synapses define a powerful distynaptic cortico-hippocampal loop. Neuron 66, 560-572.
5. Piskorowski, R., Santoro, B. and Siegelbaum, S.A. (2011). TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal
neurons. Neuron 70:495-509.