Embryological origin for autism: Developmental anomalies of the cranial nerve motor nuclei

Abstract

The underlying brain injury that leads to autism has been difficult to identify. The diagnostic criteria of the disease are not readily associated with any brain region or system, nor are they mimicked by vascular accidents, tumors, or degenerative neurological diseases occurring in adults. Fortuitously, a recent report of autism induced by thalidomide exposure provides evidence that the disease originates by an injury at the time of closure of the neural tube. The human data suggest that the initiating lesion includes the motor cranial nerve nuclei. To test this hypothesis, we first examined motor nuclei in the brainstem of a human autistic case. The autopsy brain exhibited near-complete absence of the facial nucleus and superior olive along with shortening of the brainstem between the trapezoid body and the inferior olive. A similar deficit has been reported in Hoxa-1 gene knockout mice in which pattern formation of the hindbrain is disrupted during neurulation. Alternatively, exposure to antimitotic agents just after neural tube closure could produce the observed pattern of deficits. Thus, the lesions observed in the autopsy case appear to match those predicted by the thalidomide cases in both time of origin and central nervous system (CNS) location. To produce similar brain lesions experimentally, we exposed rat embryos to valproic acid, a second teratogen newly linked to autism. Dams received 350 mg/kg of valproic acid (VPA) on day 11.5 (the day of neural tube closure), day 12, or day 12.5 gestation. Each treatment significantly reduced the number of motor neurons counted in matched sections of the earliest-forming motor nuclei (V, XII), and progressively later exposures affected the VIth and IIIrd cranial nerve nuclei. All treatments spared the facial nucleus, which forms still later. Counts from the mesencephalic nucleus of trigeminal, the dorsal motor nucleus of the vagus, and the locus ceruleus were not affected by exposure to VPA, even though these nuclei form during the period when exposure occurred. Despite its effects on the motor nuclei, valproic acid exposure did not alter the further development of the brain in any obvious way. Treated animals were robust and had no external malformations. The autopsy data and experimental data from rats confirm that CNS injuries occurring during or just after neural tube closure can lead to a selective loss of neurons derived from the basal plate of the rhombencephalon. The results add two new lines of evidence that place the initiating injury for autism around the time of neural tube closure.

Advances in behavioral genetics: mouse models of autism

“…Mice with disruptions of Hoxa1 have profound alterations in hindbrain organization, [255][256][257][258] which may reflect brainstem abnormalities observed in autism. 259,260 Evidence from family studies in human populations has suggested that HOXA1 is associated with genetic susceptibility for autism, 261,262 although results have been inconsistent. 263,264 A HOXA1-related disorder, Bosley-Salih -Alorainy syndrome, has been identified in a small patient sample, with symptoms that include delayed maturation and autism.…”

Turning heads: Development of vertebrate branchiomotor neurons

“…In cases of Pierre-Robin syndrome, patients exhibit feeding and respiratory problems, possibly due to defects in CMN development (Abadie et al, 2002). The Moebius syndrome and some forms of autism are associated with the loss of brainstem motor nuclei (Rodier et al, 1996;Bonanni and Guerrini, 1999).…”

Abnormal Fear Conditioning and Amygdala Processing in an Animal Model of Autism

“…To test this hypothesis, we assessed fear processing in the valproic acid (VPA) rat model of autism (Rodier et al, 1996). VPA is one of the teratogens implicated in causing autism in humans (Christianson et al, 1994;Williams and Hersh, 1997;Moore et al, 2000;Williams et al, 2001;Rasalam et al, 2005), when administered around the critical time period of neural tube closure (embryonic day 20-24; Arndt et al, 2005).…”

“…injection of VPA to the pregnant dam at a corresponding time of embryonic day 12.5 tends to produce a neuroanatomical and behavioral phenotype similar to the human condition. Offspring of treated dams exhibit brain stem injuries, diminished number of Purkinje cells in the cerebellum, impaired social interaction, increased repetitive behavior, increased nociceptive thresholds, increased sensitivity to complex sensory stimulation, and enhanced anxiety (Rodier et al, 1996(Rodier et al, , 1997Ingram et al, 2000;Schneider and Przewlocki, 2005;Schneider et al, 2006), all symptoms that are common to autism.…”