McAllister, A. Kimberley - University of California, Davis

研究领域

The mammalian brain requires the proper formation of exquisitely precise circuits to function correctly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. Synapses are initially established through physical contact between presynaptic axonal growth cones and postsynaptic dendrites. These rudimentary connections are subsequently transformed into the highly specified, complex structure of the mature synapse. While much has been learned about formation of the neuromuscular junction in the peripheral nervous system, surprisingly little is known about the cellular and molecular mechanisms responsible for formation, stabilization, and refinement of synapses between neurons in the central nervous system (CNS). The overall goal of our research is to investigate the cellular and molecular mechanisms of synapse formation in the developing cerebral cortex. Our primary experimental approach is to use dissociated, cultured neurons from the developing visual pathway as a model system. The formation of individual synapses in these cultures is studied using several techniques. First, the sequence of molecular events that occur during synapse formation and stabilization is investigated by imaging changes in distribution of pre- and postsynaptic proteins fused to GFP using laser-scanning confocal microscopy. Second, the sequence of events that occur physiologically as the synapse forms and stabilizes (or weakens and retracts) is determined using modified whole- cell patch clamp recording techniques. Finally, the signals that may guide synapse formation (such as neurotrophins, cell adhesion molecules, or ephrins) are studied by manipulating them at forming synapses with pharmacological agents, transgenic technology and/or transfection techniques. By combining data from these molecular and physiological approaches, we hope to construct a vivid picture of synapse formation and stabilization in the developing CNS. Currently, there are a number of specific projects being conducted in the laboratory. The most basic of these focuses on defining the sequence of recruitment of pre- and postsynaptic proteins to nascent synapses. We are also currently studying two potential modulators of synapse formation: the neurotrophins and specific forms of synaptic activity. Finally, we are also investigating whether there are defects in synapse formation that might contribute to Fragile-X mental retardation and Alzheimer's disease. In the near future, we will add multi- photon microscopy to our array of techniques in order to study the development of the geniculocortical synapse in co-cultured organotypic slices. The laboratory is currently funded by the National Institutes of Health, the Pew Foundation, the Alfred P. Sloan Foundation, the March of Dimes, and the John Merck Fund. The results of our experiments will be essential for a comprehensive understanding of the cellular and molecular mechanisms underlying the development of the cerebral cortex. It is our hope that our results will also provide insight into the molecular signals required for synaptic strengthening, a process that may be the cellular substrate for learning and memory, and for certain disease processes such as neurodevelopmental and neurodegenerative disorders.

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Barrow SL, Constable JR, Clark E, El-Sabeawy F, McAllister AK, Washbourne P. (2009) Neuroligin1: a cell adhesion molecule that recruits PSD-95 and NMDA receptors by distinct mechanisms during synaptogenesis. Neural Development 4:17 McAllister AK (2007) Dynamic aspects of CSN synapse formation. Annual Reviews of Neuroscience, in press. Sabo SL, Gomes RG, and McAllister AK (2006) Formation of presynaptic terminals at predefined sites along axons. Journal of Neuroscience, in press. Gomes R, Hampton C, El-Sabeawy F, Sabo SL, and McAllister AK. The dynamic distribution of TrkB receptors before, during, and after synapse formation between cortical neurons (2006) J Neuroscience Glynn MS and McAllister AK (2006) Quantification of protein colocalization in cultured immunostained neurons. Nature Protocols, in press. Washbourne PW, Liu X-B, Jones EG, and McAllister AK (2004) Exo/endocytic cycling of NMDA receptors during trafficking in neurons before synapse formation. Journal of Neuroscience, 24:8253-8264. Sabo SL and McAllister AK (2003) Mobility and cycling of synaptic protein-containingvesicles in axonal growth cone filopodia. Nature Neuroscience 6: 1264-1269. Washbourne P, Bennett JE, and McAllister AK (2002) Rapid recruitment of NMDA receptor transport packets to nascent synapses. Nature Neuroscience 5: 751-759. Washbourne P and McAllister AK (2002) Techniques for gene transfer into neurons. Current Opinion in Neurobiology. 12: 566-573. McAllister AK and CF Stevens (2000) Nonsaturation of both AMPA and NMDA receptors at hippocampal synapses. Proc. Natl. Acad. Sci. USA 97:6173-6178. McAllister AK (2000) Cellular and molecular mechanisms of dendritic growth. Cerebral Cortex 10: 963-973. McAllister AK, LC Katz, and DC Lo. (1999) Neurotrophins and synaptic plasticity. Annual Review of Neuroscience 22:295-318. McAllister AK, LC Katz, and DC Lo. (1997) Opposing roles for endogenous BDNF and NT-3 in regulating cotical dendritic growth. Neuron 18:767-778. McAllister AK, Katz LN, and Lo DC (1996) Neurotrophin regulation of cortical dendritic growth requires activity. Neuron 17: 1057-1064. McAllister AK, Lo DC, and Katz LC (1995) Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 15: 791-803. Lo DC, McAllister AK, and Katz LC (1994) Neuronal transfection in brain slices using particle-mediated gene transfer. Neuron 13: 1263-1268.