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The Journal of Neuroscience, June 1, 2002, 22(11):4530-4539
Interferon  Induces Retrograde Dendritic Retraction and
Inhibits Synapse Formation
In-Jung
Kim1,
Hiroko
Nagasawa
Beck2,
Pamela J.
Lein2, and
Dennis
Higgins1
1 Department of Pharmacology and Toxicology, State
University of New York, Buffalo, New York 14214, and
2 Department of Environmental Health Sciences, Bloomberg
School of Public Health, Johns Hopkins University, Baltimore, Maryland
21205
The expression of interferon  (IFN) increases after neural
injury, and it is sustained in chronic inflammatory conditions such as
multiple sclerosis and infection with human immunodeficiency virus. To
understand how exposure to this proinflammatory cytokine might affect
neural function, we examined its effects on cultures of neurons derived
from the central and peripheral nervous systems. IFN inhibits
initial dendritic outgrowth in cultures of embryonic rat sympathetic
and hippocampal neurons, and this inhibitory effect on process growth
is associated with a decrease in the rate of synapse formation. In
addition, in older cultures of sympathetic neurons, IFN also
selectively induces retraction of existing dendrites, ultimately
leading to an 88% decrease in the size of the arbor. Dendritic
retraction induced by IFN represents a specific cellular response
because it occurs without affecting axonal outgrowth or cell survival,
and it is not observed with tumor necrosis factor  or other
inflammatory cytokines. IFN-induced dendritic retraction is
associated with the phosphorylation and nuclear translocation of signal
transducer and activator of transcription 1 (STAT1), and expression of
a dominant-negative STAT1 construct attenuates the inhibitory effect of
IFN. Moreover, retrograde dendritic retraction is observed when
distal axons are selectively exposed to IFN. These data imply
that IFN-mediated STAT1 activation induces both dendritic atrophy
and synaptic loss and that this occurs both at the sites of IFN
release and at remote loci. Regressive actions of IFN on dendrites
may contribute to the neuropathology of inflammatory diseases.
Key words:
interferon ; bone morphogenetic protein-7; dendrites; sympathetic neurons; hippocampal neurons; STAT1; retrograde
transport
Copyright © 2002 Society for Neuroscience 0270-6474/02/22114530-10$05.00/0
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