Biology Reference
In-Depth Information
We have recently undertaken the study of 5-HT receptors in the biology
of axon growth and regeneration. In preliminary experiments over-
expressing Htr7 in acutely purified rat postnatal (P8) retinal ganglion cells,
a type of CNS projection neuron, we observed a decrease in total neurite
length after 2 days in culture. This effect was potentiated by addition of
5-HT and partially reversed by addition of the Htr7-selective inverse agonist
methiothepin (unpublished data). Thus,
in vitro
pharmacological and over-
expression manipulation of Htr7 has different effects on neurite length,
depending on a specific neuronal type. Such experiments, along with
Htr4/7 overexpression and knockdown, need to be conducted in other
neuronal types and ages, and in
in vivo
acute gene manipulations and axon
regeneration models.
4. MECHANISMS OF 5-HT EFFECT ON NEURITE GROWTH
What are the molecular mechanisms mediating 5-HT receptors'
effects on neurite growth? One possibility may involve modulation of neu-
ronal excitability. Neuronal stimulation is a known enhancer of neurite
growth (see Volume 105 Chapter 2) and different 5-HT receptors can reg-
ulate neuronal stimulation in opposite ways. For example, Htr1 and Htr5
receptor families are hyperpolarizing, whereas Htr2, Htr3, Htr4, Htr6,
and Htr7 receptor families are depolarizing. Furthermore, Htr3 is a
ligand-gated cation (Na
þ
and K
þ
) channel and could directly depolarize
the cell. The remaining 5-HT receptors are G protein-coupled (GPCR)
and signal through various G protein subunits and multiple secondary mes-
sengers. For example, Htr1, Htr4, Htr5, Htr6, and Htr7 modulate cAMP
activity, a prominent regulator of neurite growth (see Volume 105 Chapter
6), whereas Htr2 regulates DAG and IP
3
, which also interact with neurite
growth regulatory pathways. Regulation of local Ca
2
þ
levels is probably
the best-studied mechanism through which 5-HT could affect axon growth
(
Homma et al., 2006; Lauder, 1993; Zhang & Forscher, 2009
).
G protein subunits of the 5-HT GPCR and their downstream pathways
have been studied only scarcely in the context of 5-HT effects on neurite
growth. Htr1A was suggested to promote neurite outgrowth through G
protein subunit G
a
i(
Fricker et al., 2005
). Htr7 affects formation of dendritic
spines directly through G protein subunit G
a
12
which appears to accomplish
this through altering local Ca
2
þ
levels and modulating Rho GPTases' activ-
ities (
Kobe et al., 2012
). However, other mechanisms remain to be explored.
For example, 5-HT can regulate growth cone actin networks, Rho GTPases
