Discovery of allelic variants of HOXA1 and HOXB1: genetic susceptibility to autism spectrum disorders.

BACKGROUND: Family studies have demonstrated that the autism spectrum disorders (ASDs) have a major genetic etiologic component, but expression and penetrance of the phenotype are variable. Mice with null mutations of Hoxa1 or Hoxb1, two genes critical to hindbrain development, have phenotypic features frequently observed in autism, but no naturally occurring variants of either gene have been identified in mammals. METHODS: By sequencing regions of genomic DNA of patients with autism spectrum disorders, we detected a substitution variant at HOXA1 and an insertion variant at HOXB1, both in coding regions of the genes. Fifty-seven individuals ascertained for a diagnosis of an ASD, along with 166 of their relatives, were typed for these variants. Two non-ASD populations were typed, and the frequency of the newly identified alleles was determined in all groups. The genotypes of the ASD families were tested for conformation to Hardy-Weinberg proportions and Mendelian expectations for gene transmission. RESULTS: The frequency of the variants was 10-25% in persons of European or African origin. In the ASD families, there was a significant deviation from the HOXA1 genotype ratios expected from Hardy-Weinberg proportions (P = 0.005). Among affected offspring, a significant deviation from Mendelian expectation in gene transmission (P = 0.011) was observed. No statistically significant effects were detected when the same analyses were applied to the HOXB1 locus, but there was evidence of an interaction between HOXA1, HOXB1, and gender in susceptibility to ASDs. CONCLUSIONS: The results support a role for HOXA1 in susceptibility to autism, and add to the existing body of evidence implicating early brain stem injury in the etiology of ASDs.

Cross-sensitization between footshock stress and apomorphine on self-injurious behavior and neostriatal catecholamines in a rat model of Lesch-Nyhan syndrome.

The effects of footshock sensitization (priming), apomorphine (APO) priming and their combination on behavior and neostriatal and cortical catecholamines were examined in adult rats which had neonatally received bilateral intracerebroventricular injections with 6-hydroxydopamine (6-OHDA; a model of Lesch-Nyhan syndrome (LNS)) or vehicle (unlesioned rats). Lesioned (6-OHDA-treated) rats displayed self-biting (SB; 7/20 rats) and self-injurious behavior (SIB; 1/20 rats) during APO priming, but not during footshock priming. During subsequent acute cumulative APO dosing, 20-30% of lesioned rats primed with APO alone or footshock alone displayed SB and SIB. However, SB and SIB incidence in APO+footshock-primed lesioned rats was nearly tripled. Dopamine (DA) synthesis, metabolism and extracellular concentrations (disposition) in unlesioned rats and in cortices of lesioned animals were unaffected by priming. In lesioned rats primed with APO alone or footshock alone, only neostriatal 3-methoxytyramine (3-MT) was significantly increased. However, neostriatal DA and metabolite concentrations (and norepinephrine (NE)) were all significantly elevated in lesioned rats primed with both APO and footshock. These results confirm that neonatal 6-OHDA-induced neostriatal catecholamine depletion can be antagonized by experiential change, suggest that behavioral and neurochemical cross-sensitization between APO and footshock in such rats is unidirectional and support the view that stress can exacerbate the incidence of SIB in LNS.

Fixed-ratio discrimination training as replacement therapy in Parkinson's disease: studies in a 6-hydroxydopamine-treated rat model.

Severe 6-hydroxydopamine (6-OHDA)-induced neostriatal dopamine (DA) depletion is generally held to be irreversible. Adult rats administered 6-OHDA soon after weaning, or neonatally, respectively model Parkinson's disease (PD) and Lesch-Nyhan syndrome (LNS). Prior studies in our laboratory indicate that prolonged training on incrementally more difficult fixed-ratio (FR) discriminations can reverse 'irreversible' 6-OHDA-induced neostriatal DA depletion in adult LNS rats. The present study evaluated the effects of such training on neostriatal DA depletion and its functional consequences in adult PD and control (vehicle-injected) rats. After recovery from 6-OHDA-induced hypophagia, rats were sacrificed to assess neostriatal DA depletion magnitude, or were food-deprived and either subjected to food-maintained operant FR discrimination training or allowed to remain in their home cages. 6-OHDA treatment antagonized amphetamine (AMP)-induced increases in brief rearing behavior and locomotor activity in 3-month-old PD rats prior to training, and reduced operant response rates throughout training without affecting learning rates. One week after training, AMP-increased locomotor and brief-rearing frequencies were augmented in all groups except trained controls, and the prior inhibitory effect of 6-OHDA treatment on AMP-increased behavioral frequencies was essentially eliminated. Cumulative apomorphine (APO) dose-effect curve (0.1-3.2 mg/kg) construction 3 weeks post-training revealed that 6-OHDA treatment abolished APO-induced intense licking behavior. However, training eliminated the hyperresponsiveness of 6-OHDA-treated rats to the locomotor- and brief-rearing stimulant effects of APO but did not affect the depletion of neostriatal DA. Nevertheless, 6-OHDA-induced increases in neostriatal DOPAC/DA and HVA/DA ratios were normalized by age/food-deprivation while that of 3MT/DA was not. These findings suggest that training reduces the functional responsiveness of at least some central DA receptors, FR discrimination training could be a useful adjunct to PD replacement therapy and that the neostriatal DA-repleting action of training in 6-OHDA-treated rats depend on the age at which 6-OHDA is administered.

FR discrimination training reverses 6-hydroxydopamine-induced striatal dopamine depletion in a rat model of Lesch-Nyhan syndrome.

Five-day-old rats received 6-hydroxydopamine (6-HD; 100 micrograms base) or vehicle intracisternally. Striatal and cortical dopamine (DA) and metabolite levels were then determined when animals were three or 8.5 months of age and the latter rats had been weight-reduced for 5.5 months. In the latter animals these determinations were made 1 month following 4.5 months of home-cage confinement (untrained animals) or of food-maintained fixed-ratio (FR) discrimination training involving either a single discrimination (performance animals) or incrementally more difficult discriminations. Striatal DA levels in 3-month-old and 8.5-month-old (untrained) 6-HD-treated rats were, respectively, only 3% and 11% of those in untrained vehicle-treated animals (controls). Despite such large depletions, striatal DA levels in 6-HD-treated performance rats were 3-fold higher than those in untrained age-matched 6-HD-treated rats (i.e., were 32% of values in controls) while those in incrementally trained 6-HD-treated animals were even higher (i.e., were 60% of control values). Related changes occurred in levels of most metabolites. However, in incrementally trained rats, striatal 3-methoxytyramine concentrations were 154% of control values. Cortical DA and metabolite levels were little affected by 6-HD treatment. The present results confirm and extend our earlier observations suggesting that reversal of 'irreversible' neonatal 6-HD-induced striatal dopamine and metabolic depletion can be accomplished by environmental (training) manipulations in adult rats.

Reversal of 6HD-induced neonatal brain catecholamine depletion after operant training.

Rats received either vehicle (controls) or 100 micrograms of 6-hydroxydopamine (6HD) base intracisternally on postnatal day 5. At 3 mo of age, striatal and cortical catecholamine and metabolite levels were determined in some animals. Others were subjected to 4.5 mo of training on incrementally more difficult fixed-ratio (FR) discriminations; 2 mo later, their levels were determined. Learning was essentially unaffected by 6HD even though errors in all animals increased with increases in discrimination difficulty and 6HD had markedly depleted levels in the 3-mo-old animals. Moreover, an initial response-rate deficit in 6HD-treated rats disappeared with training. However, after training, levels in 6HD-treated rats were not only not depleted, they were as much as 661% of those in controls. These and others of our findings indicate that FR discrimination training can induce persistent increases in brain catecholamine utilization. They also appear to be the first to suggest that at least some neurochemical effects of neonatal 6HD are not necessarily irreversible, and that such a reversal can be experientially induced and possibly functionally beneficial.