In utero exposure to valproic acid (VPA) may cause symptoms related to autism spectrum disorder (ASD). An abnormal serotonergic (5-HT) system has been implicated in the etiology of ASD. In the present study, we have examined the expression and distribution of two early inducers of 5-HT neurons in rat embryos, to elucidate the prenatal development of 5-HT neurons after VPA exposure at embryonic day (E) 9.5. Whole-embryo in situ hybridization at E11.5 showed that the expression of sonic hedgehog, one of the early inducers of 5-HT neurons, was reduced around the isthmus in the VPA-exposed group. Furthermore, whole-mount immunohistochemistry of the hindbrain and quantitative analysis of 5-HT neurons in the rostral raphe nucleus (rRN) revealed that neuronal distribution in the caudal part of the rRN was narrower at E15.5 in the VPA-exposed group than in controls. Thus, the early development of 5-HT neurons was altered after VPA exposure in utero. The observed prenatal alteration may be significant in the etiology of autism.

Autism is often associated with multiple developmental anomalies including asymmetric facial palsy. In order to establish the etiology of autism with facial palsy, research into developmental abnormalities of the peripheral facial nerves is necessary. In the present study, to investigate the development of peripheral cranial nerves for use in an animal model of autism, rat embryos were treated with valproic acid (VPA) in utero and their cranial nerves were visualized by immunostaining. Treatment with VPA after embryonic day 9 had a significant effect on the peripheral fibers of several cranial nerves. Following VPA treatment, immunoreactivity within the trigeminal, facial, glossopharyngeal and vagus nerves was significantly reduced. Additionally, abnormal axonal pathways were observed in the peripheral facial nerves. Thus, the morphology of several cranial nerves, including the facial nerve, can be affected by prenatal VPA exposure as early as E13. Our findings indicate that disruption of early facial nerve development is involved in the etiology of asymmetric facial palsy, and may suggest a link to the etiology of autism.

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Astrocytes are thought to be active participants in synaptic plasticity in the developing nervous system. Previous studies suggested that axosomatic synapses decreased in number on the small cells of the rat caudal nucleus of tractus solitarius (cNTS) toward the end of the first postnatal week. Astrocytes might be involved in this phenomenon. We examined the morphological development of astrocytic processes around the small cell soma in the rat cNTS using light and electron microscopy. Glial fibrillary acidic protein (GFAP), glutamate-aspartate transporter (GLAST), and glutamate transporter-1 (GLT-1)-positive structures within the cNTS became more intensely stained as development proceeded. GLAST-positive structures encompassed calbindinpositive small cell somata after postnatal day 10. Electron microscopic observations indicated that astrocytic processes encompass the small cell soma, while the number of axosomatic synapses decreases as development proceeds. The timing for glial coverage of the small cell soma appears to be consistent with the decrease in axosomatic synapses on the small cells. These observations imply that astrocytes may participate actively in regulating the decrease of axosomatic synapses on small cells in the cNTS during postnatal development. V V C 2007 Wiley-Liss, Inc.

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