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also affect other molecular targets. Hence more direct evidence—for
example, using genetic knockdown and overexpression—is needed to eval-
uate Htr1A's potential for modulating axon regeneration. Because develop-
mental knockouts could be compensated for and because Htr1A may affect
axon regeneration without altering development, an acute conditional ma-
nipulation may be preferred to investigate Htr1A's role in axon or dendrite
regeneration and plasticity, in an appropriate model.
3.2. Htr1B/D
In primary embryonic (E15) mouse thalamic neurons cultures, selectiveHtr1B
agonist CGS-12066A maleate significantly promoted neurite extension and
branching (
Lotto, Upton, Price, & Gaspar, 1999; Persico et al., 2006
).
Htr1B knockout mice develop normally and do not display overt
morphological abnormalities in the brain (
Brunner & Hen, 1997; Saudou
et al., 1994
). However, Htr1B knockout in 5-HTT or MAOA knockout
mice, which may have increases in extracellular 5-HT at least regionally and
transiently during development, significantly reduces alterations in the
segregation of retinogeniculate projections and patterning of thalamocortical
projections (
Salichon et al., 2001; Upton et al., 2002
). Supporting a role in
axon guidance, in explant culture, 5-HT stimulation of the Htr1B/D
receptors converted the attraction exerted by netrin-1 on mouse thalamic
axons to repulsion (
Bonnin et al., 2007
).
In vivo
,
in utero
siRNA knockdown
or overexpression of Htr1B or Htr1D by electroporation altered
thalamocortical projections in different ways (
Bonnin et al., 2007
).
Together, these data suggest that during development, Htr1B/D regulate
guidance of the retinogeniculate and thalamocortical projections. Although
in vitro
data suggest that Htr1B may also promote neurite growth, such
evidence is subject to the limitations of pharmacological approaches and
needs to be verified with knockdown and overexpression, as well as tested
in other neuronal types and ages, as above. Similarly, an acute knockout/
knockdown may be needed for
in vivo
investigation of Htr1B's role in
neurite growth and plasticity, and an appropriate model
is needed for
studying its effect on axon regeneration, as above.
3.3. Htr2A/C
The Htr2A receptor is expressed in Purkinje cells, and application of DOI, a
selective Htr2A/C agonist, decreased Purkinje cell dendrites growth in
organotypic P7 rat cerebellar slice cultures after 4 DIV (
Kondoh et al., 2004
).
