Biology Reference
In-Depth Information
One further study highlights the importance of controlling the kinetics
of neurotrophic factor delivery, especially if gene therapy is to be used to
supply these agents during the clinical management of neurotrauma. Quan-
titative analysis of the morphology of regenerating adult rat RGCs following
long-term (5-8 months) rAAV2-mediated overexpression of BDNF
or CNTF revealed significant differences in dendritic architecture in these
neurons (
Rodger et al., 2012
). Further, overexpression affected not only the
transduced neurons but also the nontransduced “bystander” RGCs. Multi-
variate analysis revealed that transgenic BDNF increased dendritic field area
in all RGCs, whereas CNTF decreased complexity but only in a subset of
large (type 1 like) RGCs. In addition, cells in both transgene groups dis-
played abnormal stratification and were more than twice as likely to have
highly abnormal morphology. Such changes are likely to change the pattern
and efficacy of the afferent synaptic input to RGCs, potentially altering the
function of any conserved or reconstructed neural circuits. Similar, although
less dramatic, changes after rAAV-CNTF or rAAV-BDNF eye injections
have also been seen in RGCs in normal adult rat retina (A.R. Harvey &
J. Rodger, manuscript in preparation). As reviewed elsewhere (
Hellstr¨m
&Harvey, 2011
), the design of efficient, nonimmunogenic, regulatable pro-
moters is likely to be needed for optimal vector-mediated delivery of neu-
rotrophic factors to the injured CNS, and because local overexpression of
growth factors can alter the dendritic architecture of surviving and reg-
enerating adult neurons, there may be a need to develop more sophisticated
protocols that selectively target either the axonal or dendritic compartments.
REFERENCES
Ahmed, Z., Berry, M., & Logan, A. (2009). ROCK inhibition promotes adult retinal
ganglion cell neurite outgrowth only in the presence of growth promoting factors.
Molecular and Cellular Neuroscience
,
42
, 128-133.
Ahmed, Z., Suggate, E. L., Brown, E. R., Dent, R. G., Armstrong, S. J., Barrett, L. B., et al.
(2006). Schwann cell-derived factor-induced modulation of the NgR/p75NTR/EGFR
axis disinhibits axon growth through CNS myelin in vivo and in vitro.
Brain
,
129
,
1517-1533.
Alabed, Y. Z., Pool, M., Ong Tone, S., Sutherland, C., & Fournier, A. E. (2010). GSK3 beta
regulates myelin-dependent axon outgrowth inhibition through CRMP4.
The Journal of
Neuroscience
,
30
, 5635-5643.
Andrieu-Soler, C., Bejjani, R. A., de Bizemont, T., Normand, N., BenEzra, D., &
Behar-Cohen, F. (2006). Ocular gene therapy: A review of nonviral strategies.
Molecular
Vision
,
12
, 1334-1347.
Bai, Y., Dergham, P., Nedev, H., Xu, J., Galan, A., Rivera, J. C., et al. (2010). Chronic and
acute models of retinal neurodegeneration TrkA activity are neuroprotective whereas
p75NTR activity is neurotoxic through a paracrine mechanism.
The Journal of Biological
Chemistry
,
285
, 39392-39400.
