Biology Reference
In-Depth Information
(see below) (
Fricker, Rios, Devi, & Gomes, 2005
). Thus, both positive and
negative effects of 5-HT on neurite growth are seen
in vitro
.
In vivo
, increasing 5-HT levels in transgenic mice lacking the enzyme
monoamine oxidase A (MAOA), which breaks down 5-HT, resulted in
changes in developmental patterning in the somatosensory cortex and
altered the segregation of ipsilateral and contralateral retinal projections; how-
ever, no deficiency specific to axonal length was reported (
Cases et al., 1995,
1996; Upton et al., 1999
). Mouse knockout of 5-HT transporter (5-HTT;
SERT)—which takes up and clears 5-HT from the synaptic cleft—also did
not lead to gross morphological axonal abnormalities in brain development
(
Bengel et al., 1998; Holmes, Yang, Murphy, & Crawley, 2002
), with an
exception of alterations in the segregation of retinogeniculate projections
and patterning of thalamocortical projections, similar to the MAOA
knockout phenotype (
Salichon et al., 2001
). Together, these experiments
suggest that increased 5-HT during development does not greatly adversely
affect neurite growth beyond specific defects in axon guidance. However,
inhibition of 5-HT synthesis by DL-P-chlorophenylalanine methyl ester
hydrochloride (PCPA) treatment during embryonic rat development
decreased dendritic length and complexity in adult pyramidal neurons
(
Vitalis, Cases, Passemard, Callebert, & Parnavelas, 2007
). In contrast,
developmental depletion of central 5-HT synthesis in Pet-1 knockout mice,
which lack a majority of CNS serotonergic neurons, did not reveal apparent
defects in neurite patterning and growth in nonserotonergic systems
(
Hendricks et al., 2003
).
Together, these data suggest a varied set of potential roles for 5-HT. Cell
line data from PC12 and Neuro 2A cells is confounded by 5-HT's influence
on differentiation and may not directly affect already differentiated neurites'
growth. Primary neurons in culture demonstrate varying effects.
In vivo
experiments, however, suggest that alterations in 5-HT levels and localiza-
tion in CNS may adversely affect dendrite growth and neurite patterning
during development. Why such varying effects? We hypothesize that differ-
ences in receptor subtypes expression and localization may explain the dra-
matic differences in effects seen
in vitro
and
in vivo
.
3. 5-HT RECEPTORS SUBTYPES AFFECTING NEURITE
GROWTH
Which receptor subtypes mediate 5-HT's effects on neurite growth?
Underlying 5-HT's functional diversity are seven classes of inhibitory and
excitatory receptors comprised of 13 distinct subtypes in humans and an
