Synaptic loss is a common feature of many acute and chronic neurological diseases and may occur even in the absence of significant neuronal death. This suggests that synaptic disruption can be a primary cause of dysfunction and thus the long-term stability of synaptic connections may be critical in maintaining the integrity of the nervous system.
Our laboratory is interested in elucidating cellular and molecular processes controlling the stability of synaptic connections. Specifically, we are interested in learning how synapses are maintained in the intact brain, how their microenvironment affects their turnover rate, what molecules play a role in regulating synaptic stability and how synaptic connectivity is altered following acute brain injury and chronic neurodegeneration .Our long-term goal is to understand common mechanisms that lead to synaptic disruption in various neurological diseases and to use that knowledge to design therapeutic interventions to reestablish neuronal connectivity.
One focus of the laboratory is Alzheimer’s disasese (AD). Specifically, we investigate how interactions between neurons, microglia and amyloid plaques lead to neuronal circuit disruption in AD and how vascular dysfunction interacts with AD pathology, neuroinflamation and ultimately synaptic injury.
To accomplish these goals, we have developed methods that allow us to repeatedly image individual neurons and synapses as well as other cell types such as microglia, astrocytes and blood vessels in the brain of living mice. We use multi-photon microscopy to follow the same structures over periods of up to several months in a relatively non-invasive fashion. This allows us to investigate in vivo the dynamic interactions between different cell types. Other experimental methods used in the laboratory are time-lapse multiphoton and confocal imaging of brain slices, immunohistochemistry, brain slice labeling by ballistic delivery of fluorescent dyes, basic molecular biology and cell culture, lentiviral vector expression of fluorescent molecules, calcium imaging and stereotaxic surgery.
Publications:
Tsai J, Grutzendler J, Duff K, Gan WB. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci. 7, 1181-1183, 2004.
J.S. Coggan , J. Grutzendler ,D . Bishop, J. Heym , W-B. Gan ,J.W. Lichtman . Age-Associated Synapse Elimination in Mouse Parasympathetic Ganglia. Journal of Neurobiology 2004 Aug;60(2):214-26. (JSC and JG contributed equally)
J. Grutzendler , J. Tsai and W-B Gan . Rapid labeling of neuronal populations by ballistic delivery of fluorescent dyes. Methods 2003. May 30(1). 79-85
J. Grutzendler, N. Kasthuri, W-B. Gan . Long-term dendritic spine stability in the adult cortex. Nature 19/26 Dec, 2002 812-816
B. Nadarajah , JE Brunstrom , J Grutzendler, R.O.L. Wong, A.L. Pearlman. Two modes of radial migration in early development of the cerebral cortex. Nature Neuroscience. 4(2), Feb, 2001 143-150
J Grutzendler and J.C. Morris. Cholinesterase Inhibitors for Alzheimer Disease. Drugs, 2001; 61(1): 41-52
W-B Gan , J Grutzendler, W-T Wong, R.O.L. Wong, and J.W. Lichtman Multicolor " diolistic " labeling of the nervous system using lipophillic dye combinations. Neuron 2000 Aug;27(2):219-25 (WBG and JG contributed equally)
Grutzendler J, Gan W-B. Long-term two-photon transcranial imaging of the living mouse brain. In: Imaging Neurons. A Laboratory Manual. Editors: Yuste R et al. (2004) (In press).
