Projects for graduate students and UROPs are currently full - please check back soon for openings.
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Projects for graduate students and UROPs are currently full - please check back soon for openings.
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During development, the brain's excitatory connections become activated as latent synapses are converted to functional ones. Where to begin the search for what instigates this "turning on" has remained largely unresolved, which could be partially due to an incorrect assumption about what is deficient during the synapse's "off" state in the first place. It is commonly believed that synapses are initially non-functional due to a postsynaptic deficit of AMPA receptors for the binding of excitatory neurotransmitter. Recent work by our lab shows that this may not be the case, that these "immature" synapses actually have perfectly functional receptors, and that the deficit rendering the synapse "silent" could in fact be at the presynaptic locus. Particularly, we found that interference with presynaptic SNARE-mediated vesicle fusion can revert functional synapses back to "silent" ones. With this realization in hand, the lab is searching for a presynaptic mechanism that initiates the molecular switch from immature to functional transmission.
See also: Renger JJ, Egles C, Liu G (2001) A developmental switch in neurotransmitter flux enhances synaptic efficacy by affecting AMPA receptor activation. Neuron 29:469-84. |
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Once synapses have been formed, we are also interested in how their strength can be modulated to confer transmission that is not only functional, but meaningful from an information-processing perspective. Since glutamate receptors in postsynaptic membrane translate released transmitter into postsynaptic activity, modulating the number and properties of glutamate receptors can play a fundamental role in the process of synaptic plasticity. We are thus examining several mechanisms by which activity regulates AMPA receptor synthesis and insertion, as well as post-translational mechanisms by which it regulates receptor efficacy via (de-)phosphorylation. Given that synaptic plasticity seems increasingly irreducible into discrete pre- and postsynaptic mechanisms, we are also looking at the effects of presynaptic transmitter release on postsynaptic modifications. Our iontophoresis methods allow us to define arbitrary stimulation to postsynaptic boutons, effectively mimicing presynaptic terminals with parameters of our choosing. We are also exploring methods for quantifying presynaptic release, so that we can examine the reciprocal question of how postsynaptic changes translate into presynaptic alterrations. By considering both sides of the synapse as a unified domain of plasticity, we hope to better discern the modifications at each side of the synapse, as well as the crosstalk that governs them.
See also: Cottrell JR, Dubé GR, Egles C, Liu G (2000) Distribution, density, and clustering of functional glutamate receptors before and after synaptogenesis in hippocampal neurons. J Neurophysiol. 84:1573-87. Liu G, Choi S, and Tsien RW (1999) Variability of neurotransmitter concentration and non-saturation of postsynaptic AMPA-type glutamate receptors at synapses in hippocampal cultures and slices. Neuron 22:395-409. Liu G and Tsien RW (1995) Properties of Synaptic Transmission at Single Hippocampal Synaptic Boutons. Nature 375:404-408. |
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| The factors that induce a cell to create new synapses are important for understanding development and regeneration after neuronal injury. Impairment of new synapse formation may play an important role in pathological processes such as Alzheimer's disease and aging. Understanding the genetic and regulatory processes that govern synapse formation will certainly help to identify new therapeutic agents for the treatment of these ailments. In addition to using gene knockout animals and transfection in cultured neurons, the lab is establishing a new functional screening system to study how selective enhancement or attenuation of gene expression affects activity-dependent synapse formation.
See also: Fan G, Egles C, Sun Y, Minichiello L, Renger JJ, Klein R, Liu G, Jaenisch R (2000) Knocking the NT4 gene into the BDNF locus rescues BDNF deficient mice and reveals distinct NT4 and BDNF activities. Nature Neurosci. 3:350-7. Tang YP, Shimuzu E, Dubé GR, Rampon C, Zhuo M, Liu G, and Tsien JZ (1999). Superior learning and memory in mice with enhanced NMDA-mediated coincidence detection. Nature 401: 63-69.
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| The strength of synapses in a given neuron are scaled together, presumably in order to preserve the information capacity of the neuron and possibly to refine its contribution to network dynamics. Projects have recently been initiated in the lab to examine the properties of this scaling: What patterns of activity induce the changes, and what are the cellular messengers and synaptic machinery that make such global refinement possible? We hope to bring genetic manipulations, poly-synaptic stimulation and whole-cell functional mapping to bear on resolving the molecules and principles that may be at work. |  |
| Progress at the level of the synapse and cell have given some hints into rules that may extend to the network level - properties that may subserve the refinement of network weights and the stabilization of global firing. With a successful interface between cultured networks and our new multi-electrode array, it may be possible for us to do preliminary explorations into these mechanisms. Our initial goal would be to culture networks under long-term stimulation protocols of several days. Alternatively, we could culture the network in various inhibitors and enhancers of activity, and observe the result for network-wide synaptic efficacy and number. More advanced studies could monitor putative poly-synaptic mechanisms such as the spread of LTP from induced sites to neighboring sites. Current challenges involve inducing configurable connectivity and decoding network activity computationally. It is our hope that principles from lower levels might prove scalable to the network level, and that studying synaptic plasticity across multiple cells simultaneously might lead to a better intuition for the principles operating at lower levels.
See also: Holmes TC, de Lacalle S, Su X, Liu G, Rich A, Zhang S (2000) Extensive neurite outgrowth and active synapse formation on self-assembling peptide scaffolds. Proc Natl Acad Sci U S A. 97:6728-33.
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