Research in the Smith laboratory has focussed on mechanisms of neural circuit development and function.  Most of this work has involved devising new electrophysiological and optical methods then using those new methods to open new areas to exploration.  The links below lead to sketches of overlapping research areas where Smith lab work has had some influence.

Burst Modeling

Smith’s doctoral research, carried out in collaboration with fellow graduate student Stuart Thompson, resulted in the first dynamic simulation of neuronal burst firing.  This simulation was based on representations of six variable ionic conductances, each characterized through voltage clamp analysis, and the first published computational model of intracellular Ca dynamics.  [More...]

Ca Ion Dynamics

Smith introduced the first model of intracellular Ca ion dynamics with his doctoral thesis (1977) and postdoctoral work (1977-1980).  This work included development of Ca measurement techniques to enable early empirical tests of Ca model predictions.  The lab has continued to introduce new methods and protocols for imaging Ca dynamics, recently including PhD student Cris Niell’s pioneering use of in vivo Ca imaging to map visual receptive fields in developing zebrafish.  [More...]

Presynaptic Ca

Collaborations with Bob Zucker, Milton Charlton, George Augustine and JoAnn Buchanan in the early 1980’s established that presynaptic transmitter release at the squid giant synapse depends on intracellular Ca ions in a steeply cooperative fashion, with little or no direct dependence on membrane potential.  Later work also established tight, active-zone localization of presynaptic Ca channels.   [Movies]

NMDA Ca Signaling

A collaboration with Amy MacDermott, Mark Mayer, Gary Westbrook and Jeff Barker (1985) resulted in the first demonstration of Ca influx through the glutamate-operated NMDA receptor-channel.  This NMDA Ca permeability has proven fundamental to many aspects of neural circuit development and to understanding most known forms of synaptic plasticity.  [More...]

Growth Cone Dynamics

Smith developed early digital video methods that enabled pioneering studies of the dynamics of actin-based and microtubule-based motility of neuronal growth cones.  Smithlab postdoc Paul Forscher used these methods to explore the actin dynamics that shape axon growth and the motility of the neuronal growth cone.  Forscher’s work began in 1985 as a collaboration with Prof. Len Kaczmarek and electron microscopist JoAnn Buchanan, and continued until the Smithlab’s late 1989 relocation to Stanford.  Later work extends to in vivo observations of growth cones, axon growth and synapse formation in vivo in zebrafish embryos and larvae.  [Movies]

Astrocytic Ca Signaling

Graduate student Steven Finkbeiner and Smithlab postdocs Ann Cornell-Bell and Mark Cooper were the first to describe astrocytic Ca waves and oscillations (1988-89).  Graduate students John Dani and Alex Chernjavsky (1992) later established that astrocytic Ca signals could be triggered by neuronal activity.  Such Ca signals are now believed to couple neural activity to brain blood flow and may also shape neural development and functional activity patterns.  [Movies]

Dendritic Filopodia and Synaptogenesis

Work in collaboration with Craig Jahr (1988-89) suggested that dynamic dendritic filopodia could mediate activity-dependent synapse formation, and that motile filopodia are precursors of dendritic filopodia.  Later work by postdocs Monica Cooper, Michael Dailey, Noam Ziv, James Jontes, Martin Meyer and graduate student Cris Niell (1989 – 2005) provided further evidence in support of these ideas.  [Movies]

Activity and Circuit Development

Smith lab interests in NMDAR Ca fluxes and regulation of growth cone and dendrite motility were motivated originally by curiosity about about how neural activity activity could exert its strong influences on neural circuit development.  The Smith lab has developed and applied many new optical methods, and used them to gain breakthrough biological insights.  [More...]  

Synaptic Vesicle Dynamics

Postdoc Timothy Ryan was the first to demonstrate the usefulness of Betz’ FM dye synaptic vesicle probe for the study of mammalian CNS synapses.  A long series of Smith laboratory experiments (1992-2006) included the first single-vesicle recordings and provided new information on many key properties of synaptic vesicle recycling dynamics.

Transport Packets

Postdoc Mark Cooper in 1990 developed an early ultra-low-light live cell imaging protocol that provided the first dynamic glimpse of membrane traffic through the Golgi apparatus.  These experiments revealed traffic of membrane packets of highly variable size and shape.  Later experiments on hippocampal neurons by MD/PhD student Susanne Ahmari revealed similarly pleomorphic membrane “transport packets” transporting synaptic proteins to sites of synaptogenesis.

Synaptotropic Arbor Growth

Smithlab postocs Sue Pike (1993-1996) and Jamie Jontes (1998-2005) developed techniques for the first in vivo time-lapse imaging of synapse formation. PhD student Cris Niell and postdoc Martin Meyer applied two-photon microscopy and genetic labeling methods to observe the dynamic relationships between dendritic arbor growth and synaptogenesis in developing optic tectum of larval zebrafish.  Their observations provided the first vital imaging evidence for synaptotropic guidance of dendritic arbor growth.  [Movies]

Research 1977-Present