Steven A. Siegelbaum, PhD

We are interested in the molecular and cellular mechanisms underlying electrical signaling and synaptic transmission in the nervous system, and how these electrical signals give rise to complex behaviors. We focus on how ion channels and synaptic transmission regulate information flow in the cortico-hippocampal circuit, which plays a critical role in learning and memory. One area of research explores the role of the hyperpolarization-activated cation channels (the HCN channels) in regulating dendritic integration of excitatory and inhibitory synaptic inputs. We found that genetic deletion of the HCN1 channel from hippocampus enhances synaptic excitation, the induction of long-term plasticity and, surprisingly, spatial learning and memory. As these channels have also been implicated in various neurological and psychiatric diseases, we are now examining the molecular mechanisms that regulate HCN1 channel expression and trafficking in both normal and disease states. A second project examines the role of the CA2 subregion of the hippocampus, an area first identified in 1934 but which has received little attention over the past 80 years. We have developed a mouse like that enables us to selectively inactivate CA2, which we find produces a very specific deficit in the encoding of social memory, the ability of an animal to recognize and remember a conspecific. We are now examining the CA2 neural circuitry in more detail to determine how this region participates in memory encoding. As data from individuals with schizophrenia and autism spectrum disorders suggest the presence of alterations in the CA2 region, we are using mouse models of neuropsychiatric disease to explore the possible role of altered CA2 function in the social endophenotypes of these disorders.