The regulation of synaptic transmission. In particular we are
interested in the reciprocal signaling between synapses and astrocytes
that is mediated by the release of chemical transmitters and how
astrocytes regulate synapses development and function.
Fluorescence microscopy, confocal microscopy, near-field microscopy,
electrophysiology, patch clamp recording, calcium imaging, photolytic
uncaging, cell and tissue culture, cell and molecular biology.
My research laboratory is interested in understanding the dynamic
regulation of synaptic transmission and in elucidating the roles
of glial cells in controlling the synapse. In many regions of
the central nervous system it is apparent that synapses are tripartite
structures in which in addition to the pre and postsynaptic terminal,
the astrocyte (a sub-type of glial cell) acts as a third element
that wraps around the synaptic structure. Recent studies are changing
the view of the role of astrocytes in synaptic transmission. It
is now clear that synaptic activity regulates calcium levels in
astrocytes, and as a consequence of elevated calcium, we have
demonstrated that astrocytes release the chemical transmitter
glutamate onto the synapse to modulate synaptic transmission.
In order to understand the role of the astrocyte in the control
of the synapse we are using photolysis to manipulate calcium levels
within astrocytes while monitoring synaptic transmission. As another
approach to study this complex system, we have developed selective
inhibitors of the astrocytic glutamate release pathway and are
using viral vectors to manipulate the release of this transmitter
to determine the role of these glial cells in information processing.
Using the hippocampal slice preparation (see figure) and optical
approaches, we have recently demonstrated that transmitter-evoked
calcium elevations in an astrocyte propagating to neighboring
astrocytes as a calcium wave. This raises the possibility that
a synapse could signal to neighbors by way of calcium signal that
spreads through an astrocytic intermediate.
In addition to multi-cellular studies of the synapse, we also
investigate the functional sub-structure of synapses using scanning
probe microscopy. We have previously studied channel organization
using atomic force microscopy and are currently using biological
near-field microscopy, with optical resolution of 50 nm, to probe
the workings of the synapse. Using this high-resolution system
we are studying the local microdomains of calcium accumulation
beneath activated calcium channels with the long-term objective
of visualizing individual molecules within functional synapses
to unravel the mysterious workings of this essential structure
of the nervous system.
Haydon,
P.G. (2001). Glial: Listening and Talking to the Synapse. Nature
Reviews Neuroscience. 2: 185-193.
Araque,
A., Carmignoto, G., and Haydon, P.G (2001). Dynamic Signaling
Between Astrocytes and Neurons. Annual Reviews of Physiology.
63: 795-813.
Doyle, R.T., Szulzcewski, M.J., and Haydon, P.G. (2001) Extraction
of near-field fluorescence from composite signals to provide high
resolution images of glial cells. Biophys.J. 80: 2477-82.
Parpura,
V., and Haydon, P.G.(2000) Physiological astrocytic calcium levels
stimulate glutamate release to modulate adjacent neurons. Proc.
Natl. Acad. Sci. USA 97: 8629-8634.
Araque,
A., Li, N., Doyle, R.T. and Haydon, P.G. (2000) SNARE protein-dependent
glutamate release from astrocytes. Journal of Neuroscience
20: 666-673.
Araque,
A., Parpura, V., Sanzgiri, R. P., and Haydon, P.G. (1999) Tripartite
Synapses: Glia, the unacknowledged partner. Trends in Neurosciences.
22: 208-215.
Araque,
A., Sanzgiri, R.P., Parpura, V., and Haydon, P.G. (1998) Calcium
elevation in astrocytes causes an NMDA receptor-dependent increase
in the frequency of miniature synaptic currents in cultured hippocampal
neurons. J. Neuroscience 18: 6822-6829.
Parpura,
V., Basarsky, T.B., Liu, F., Jeftinija, S., Jeftinjia, S., and
Haydon, P.G. (1994) Glutamate-mediated astrocyte-neuron signaling.
Nature 369: 744-747.
