Steven Siegelbaum, PhD

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 during memory storage. 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 contribution of CA2 pyramidal neurons to learning and memory and neuropsychiatric disorders. Although the CA2 region of the hippocampus was identified over 75 years ago, we know little about its cellular properties and role in learning and memory. We recently found that CA2 pyramidal neurons have a unique set of electrical and synaptic properties that enable these cells to form the nexus of a powerful disynaptic circuit that directly links cortical input to hippocampal output, bypassing the more classical route of hippocampal information flow. Studies in humans suggest that CA2 neurons may play a unique role in generating seizures during epilepsy; this area also shows distinct changes in patients with schizophrenia and bipolar disorder. We have generated a mouse line that now enables us to examine directly the role of CA2 in both normal learning and memory and in mouse disease models.