Fetal alcohol exposure reduces serotonin innervation and compromises development of the forebrain along the serotonergic pathway.

BACKGROUND

We reported previously that a moderate level of fetal alcohol treatment reduces the birth, maturation, and migration of serotonin (5-HT) neurons at embryonic days 11 to 15 (E11-E15). Because 5-HT is known as a differentiation signal for forebrain development, we investigated whether alcohol affects 5-HT innervation to the developing brain and how the target brain areas grow as they receive 5-HT innervation between E15 and E18.

METHODS

Pregnant dams were divided into three groups and treated from E7 to E15 or E18 with one of the following conditions: (1) liquid diet that contained 25% ethanol-derived calories (ALC), (2) isocaloric liquid diet pair-fed (PF), or (3) chow fed (Chow). The 5-HT immunostained (5-HT-IM) fibers and size of brain areas were examined as an index of growth along the ascending 5-HT pathway.

RESULT

We found that 5-HT-IM fibers innervate the brain regions specifically under active differentiation and that there were three sets of correlated dysmorphology in the ALC group as compared with those of the PF and Chow groups. The three sets are as follows: (1) fewer 5-HT-IM fibers in the medial forebrain bundle and along the projecting pathway through the hypothalamus, septal nucleus, frontal and parietal cortices, and subiculum/hippocampus; (2) underdevelopment of the brain regions along 5-HT fiber projections; and (3) underdevelopment of somatosensory thalamocortical projections, which are known to transiently express 5-HT transporters and to be regulated by 5-HT. No such differences were found between the PF and Chow groups.

CONCLUSION

We found that fewer 5-HT fibers grew in the embryos that were exposed to alcohol. As forebrain regions differentiated along the 5-HT projection, we found two reductions: (1) the growth of brain regions along 5-HT projection and (2) the growth of the thalamocortical sensory projection regulated by 5-HT. The reduced 5-HT innervation is in agreement with our previous observation of fewer 5-HT neurons. The subsequent retardation of forebrain growth and sensory thalamocortical fibers along the pathway of reduced 5-HT projection is consistent with the role of 5-HT as a signal for forebrain differentiation.