Neuroscience Graduate Program at UCSF
Interactions between Neurons and Glia that are Required for the Proper Development and Function of the Nervous System
My laboratory is interested in the interactions between neurons and glia that are required for the proper development and function of the nervous system. To study these interactions we use a variety of techniques including purification of neurons and glia for cell culture, patch clamp recording from neurons both in culture and in slices, and gene chip and molecular techniques to look at genes and proteins that are regulated by neurons and glia. Using these techniques we have begun to identify both extrinsic signals produced by glial cells and intrinsic signals produced by neurons that regulate synapse number and function. Currently we are focusing on three main questions in the lab: 1) What extrinsic glial-derived signals regulate synapse number on neurons? 2) What intrinsic neuronal signals regulate synapse number? And 3) What signals and proteins control normal synaptic development between the retina and the brain?
What extrinsic glial-derived signals regulate synapse number on neurons? One technique we use to examine cell-cell interactions is to purify retinal ganglion cells (RGCs) and RGC target neurons to examine the number and function of synapses that form in vitro. Using these techniques we have discovered a novel role for a type of glial cell, the astrocyte, in regulating synapse number and function. Astrocytes release soluble signals that are essential for synapse formation and function. We have further characterized the astrocyte-derived signal that regulates synapse number and have uncovered a novel signaling pathway between neurons and glia. We have recently found that astrocytes release proteins called thrombospondins that play important roles in regulating synapse formation both in vitro and in vivo. We are continuing to examine how thrombospondins regulate synapse number on neurons.
What intrinsic neuronal signals regulate synapse number? We have recently found that newly-generated E17 RGCs are able to form but not receive synapses. Dendrite growth is not sufficient to trigger receptivity, but rather the ability of newly-generated RGCs to receive synapses is acquired at E19 in response to direct contact by neighboring cell types. Thus, embryonic RGCs are not born with the intrinsic competence to receive synapses but irreversibly acquire this ability in response to contact-mediated signals. We are further characterizing the cell-cell interactions that regulate synapse receptivity during development and what genes change over this short two-day period that allow neurons to receive multiple synapse.
What signals and proteins control normal synaptic development between the retina and the brain? Using our in vitro system of purified neurons we have begun to identify novel gene products that play a role in synaptogenesis in the visual system. We have recently identified a family of proteins with homology to C-reactive protein that are essential for normal pattern of connections between the retina and the thalamus. We are continuing to investigate the mechanisms and function of these proteins in synaptogenesis.
Ullian, E.M., and Barres, B.A. (1998) The Schwann song of the glia-less synapse. (Review) Neuron 21: 651-652.
Kaplan M, Cho M, Ullian, EM, Isom L, Levinson R, Barres B (2001) Differential control of clustering of the sodium channels Nav1.2 and Nav1.6 at developing CNS nodes of Ranvier. Neuron 30, 105-119.
Ullian, E.M., Sapperstein, S., and BA Barres (2001) Control of synapse number by glia. Science 291: 657-61.
Ullian, E.M., Christopherson, K.S., Barres, B.A. (2003) A Role for Glia in Synaptogenesis. (Review) Glia 47: 209-216.
Ullian E.M.*, Harris B.T.*, Wu A, and B.A. Barres (2004) Schwann cells strongly promote synapse formation by spinal motor neurons in Culture. MCN 25:241-51.
Christopherson K*, Ullian E.M.*, Stokes, C.A., Mullowney C.E., Hell J.W., Agah A., Lawler J., Mosher D., Bornstein P., and Barres B.A. (2005) Thrombospondins are astrocyte-derived proteins that promote CNS synaptogenesis. Cell, 120:421-433.
Lisa Bjartmar, Andrew D. Huberman*, Erik M. Ullian*, Xiaoqin Lu, Weifeng Xu, Jennifer Prezioso, Caleb Stokes , Richard Cho, Paul Worley, Robert C. Malenka 6, Sherry Ball, Neal S. Peachey, Barbara Chapman, Masaru Nakamoto, Ben A. Barres and Mark S. Perin (2005) Neuronal Pentraxins Mediate Synapse Strengthening Required for Process Refinement in the Developing Visual System. Neuron, under revision.