Morphological abnormalities of embryonic cranial nerves after in utero exposure to valproic acid: implications for the pathogenesis of autism with multiple developmental anomalies

Abstract

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.

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder

“…In addition, a delay in eye-opening was observed in the VPA-treated animals ( Figure 1B) which may be attributable to the impaired/delayed craniofacial nerve development that is typical in this animal model of ASD (Rodier et al, 1996;Tashiro et al, 2011). No other gross developmental abnormalities were observed in VPAexposed animals.…”

Increased sociability and gene expression of oxytocin and its receptor in the brains of rats affected prenatally by valproic acid

“…impairment related to autism have used similar number of litters as we used in our study (Bambini-Junior et al, 2014;Martin and Manzoni, 2014;Miyazaki et al, 2005;Oyabu et al, 2013;Walcott et al, 2011;Tashiro et al, 2011;Snow et al, 2008;Tsujino et al, 2007). The elevated level of behaviour reflecting fear of the adult male used as the stranger rat was not observed.…”

The placental interleukin-6 signaling controls fetal brain development and behavior

“…Intriguingly, injection of VPA between E11.5 and 12.5 leads to reduction of motor neuron number in the trigeminal motor nucleus in rat pups (Rodier et al, 1996). Furthermore, VPA injection decreases immunoreactivity of neurofilaments in the trigeminal nerves of the embryo (Tashiro et al, 2011). Collectively, these studies suggest a possible mechanism by which MIA and other maternal insults could perturb development of trigeminal innervations.…”