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for possible axon growth-related phenotypes. Furthermore, 5-HT from the
circulation may provide some stimulation. Thus, direct manipulations of
5-HT levels need to be considered with caution.
Fourth, most of the
in vitro
data were collected using pharmacological
approaches. As such, they are subject to general limitation of the drugs
acting nonspecifically on other molecular targets. Combined and acute
conditional gene manipulation approaches are needed to validate that
in vitro
effects are in fact mediated by the proposed 5-HT receptor. Fur-
thermore, careful reevaluation is needed by independent groups, and
effects need to be tested in multiple types of CNS neurons, as well as dur-
ing embryonic and postnatal ages, since axon regeneration capacity
declines after birth in mammalian CNS (
Goldberg, Klassen, Hua, &
Barres, 2002
). Importantly,
in vitro
experiments should be conducted
using appropriate cultures. Many of the nonmammalian species and pe-
ripheral nervous system neurons do not lose axon regeneration capacity
in adulthood, and mammalian cell lines do not sufficiently resemble ma-
ture CNS neurons. Furthermore, dissociated brain tissue contains non-
neuronal cell types which could either mediate the effects of treatment
or counteract them. Furthermore, brain-derived cultures often contain
interneurons which may not grow long neurites and thus could poten-
tially confound the results, and even axon projecting neurons may be
of different types—for example, from different cortical layers—and ex-
press different 5-HT receptor subtypes accordingly. Thus, for
in vitro
ex-
periments, identified and/or purified neuronal types or even subtypes
may produce the best and most interpretable results.
6. CONCLUSION
5-HT can elicit varying effects on neurite growth in mammalian
CNS, suggesting a need for further investigation in axon regeneration
models, ideally using acute genetic manipulations. Given the complexity
of receptor subtype-specific signaling and the diversity of neuronal types,
combining manipulation of growth-promoting and growth-suppressing
5-HT receptor signaling in specific neuronal types might harness seemingly
opposing effects of 5-HT receptors on neurite growth for promoting axon
regeneration. Such models may be critical to the investigation of 5-HT neu-
romodulatory roles in other systems. Indeed widespread effects of 5-HT on
dendritic density, synaptogenesis, establishment of neural networks, and
corresponding behavioral and psychiatric phenotypes might depend on
