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Journal of Neuroscience, Vol 16, 1759-1769, Copyright © 1996 by Society for Neuroscience
The effects of growth factors on the survival and differentiation of cultured dentate gyrus neurons
DH Lowenstein and L Arsenault
Department of Neurology, University of California, San Francisco 94143, USA.
Dentate granule cells (DGCs) are the principal cell population of the
hippocampal dentate gyrus, and granule cells provide the main excitation to
the hippocampus proper via their mossy fibers axons. Although it is well
established that granule cells express various growth factors and growth
factor receptors, the functional effects of growth factors on the normal
development and response to injury of granule cells are relatively unknown.
To address this question, primary cultures enriched in DGCs were prepared
by microdissecting hippocampal slices from neonatal rats and growing
dissociated cells in defined media with added nerve growth factor,
brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3),
neurotrophin-4/5 (NT4/5), ciliary neurotrophic factor, basic fibroblast
growth factor (bFGF), or vehicle. The effects on cell survival and
morphology were quantified by studying neuron-specific
enolase-immunostained cells at various time points, plating densities, host
ages, and growth factor concentrations. BDNF or bFGF significantly
increased both neuronal survival and differentiation by 30-80% compared
with control cultures. Maximal effects were observed at relatively longer
time points (5-12 d), with younger cells (postnatal day 3-5) and at lowest
plating densities. Addition of a trkB- IgG fusion protein that blocks the
activity of BDNF or NT4/5 inhibited the effects of BDNF and attenuated the
differentiation of cells cultured at high plating densities. Furthermore,
treatment of cultures with the kinase inhibitor K252b specifically blocked
the effects of BDNF, suggesting involvement of trkB (the high-affinity BDNF
receptor) in BDNF-induced differentiation. These results show that growth
properties of cultured neonatal DGCs are influenced by exogenously applied
BDNF or bFGF in a time-, age-, and density-dependent manner. The effect of
plating density suggests an endogenous expression of growth factors in
these culture conditions, and this is mediated in part by endogenous BDNF
acting via a tyrosine kinase receptor. Combined with previous work showing
that various growth factors and their receptors are expressed by DGCs,
these findings provide strong support for the hypothesis that BDNF and bFGF
influence both the growth and development of DGCs in vivo.
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