Over the years, a major focus of our research has been to elucidate events that guide the development of synaptic connectivity in the living brain. The approach that we use is to image neurons in intact, non-mammalian vertebrate embryos as a means to provide new insight into the cellular, molecular, and activity-dependent processes that guide synaptogenesis in the central nervous system. Xenopus laevis tadpoles offer a uniquely accessible model system in which dynamic events can be studied because of the translucency of the embryos and because of their accessibility to experimental manipulation. The Xenopus visual system has provided us with a unique model system to study the molecular basis of developmental connectivity in vivo. In vivo time-lapse imaging studies from our laboratory have demonstrated that a process of iterative formation and elimination of synapses and neuronal branches guides synaptogenesis and is responsible for the selective stabilization of those synapses that are maintained during development. We have also used the Xenopus visual system as a model to demonstrate that the neurotrophin brain-derived neurotrophic factor (BDNF) influences synapse formation and synapse stabilization in central neurons in vivo. BDNF is a potent modulator of multiple aspects of brain development and is involved in the control of synaptic function in most vertebrate species. The work performed in my laboratory during the last couple of years has further established key mechanisms by which BDNF controls the development of retinotectal synaptic connectivity. Our work established that BDNF acts cell-autonomously, specifically on presynaptic retinal neurons to; 1) control the transition from growth cone morphology to branching axons, 2) control the stability of axon branches and synapses, and 3) control synaptic function by controlling the ultrastructural composition of synapses and the synaptic vesicle pool. Moreover, we have recently demonstrated that in the retinotectal system, BDNF acts presynaptically but has secondary effects on postsynaptic neurons. Specifically, our studies demonstrate that BDNF has an indirect influence on the morphology and synaptic connectivity of tectal neurons, the postsynaptic targets of retinal ganglion cells (RGCs), and that these effects are delayed with respect to those on RGC axons. In addition, our time-lapse imaging studies show that the dynamic behavior of tectal neuron dendritic arbors (as well as synapse dynamics) parallels the behavior of RGC axons under normal conditions and that this process is suceptible to alterations in glutamate receptor function. Thus, by using the visual system of Xenopus tadpoles as an in vivo model our group has provided unique evidence on how dynamic is synapse formation and stabilization and has demonstrated both permissive and instructive roles for BDNF during synaptogenesis in living embryos. More recent studies of our laboratory have focused on the differential cellular mechanisms by which BDNF and the axon guidance molecule netrin-1 influence pre- and post-synaptic connectivity in the developing brain, the impact of maternal fatty acid deficiencies for proper neuronal development, and understanding the relationship between environmental signals and the genetic control of BDNF expression and function, as well as its potential neuroprotective roles upon brain damage. By studying how developmental molecular signals interact to control the structural and functional plasticity of the developing brain we aim to provide valuable insights into fundamental mechanisms of synaptogenesis, and to advance the understanding of development deficiencies that can affect brain function.
University of California, Irvine
1230 McGaugh Hall
Mail Code: 4550
Irvine, CA 92697
Fax: (949) 824-2447