Neurobehavioral Anomalies Research Articles

A Comparative Survey of Carbamate‐Oxime Efficacy Against the Lethal Effects of Soman (GD) in Guinea Pigs.

The effectiveness of various carbamate-oxime combinations was evaluated against GD-induced pathophysiology in guinea pigs chronically instrumented for the monitoring of EEG, diaphragm EMG, and ECG. Animals were pretreated with either a tertiary (physostigmine, PHY; 0.015 mg/kg, im) or a quaternary (pyridostigmine, PYR; 0.026 mg/kg, im) carbamate 30 min prior to GD intoxication (2xLD50; 52 μg/kg, sc). Seconds after GD, the animals were given i) 2-PAM (25 mg/kg, im), ii) HI-6 (125 mg/kg, ip), or iii) MMB4 (26.1 mg/kg, im) and an im mixture of methylatropine (2 mg/kg) and scopolamine. HBr (0.1 mg/kg). Group 1 (PHY/MMB4) and 2 (PYR/MMB4) animals displayed mild degrees of dystonia/tremor but were asymptomatic 24 hr post-GD. Groups 3 (PHY/HI-6) and 4 (PYR/HI-6) showed more severe neurobehavioral anomalies (prolonged atonia, tremor, and incapacitation). Group 3 animals all survived 24 hr later. In Group 4, 50% of the animals seized and 17% died. Group 5 (PHY/2-PAM) and 6 (PYR/2-PAM) animals all showed extended periods of incapacitation, severe neurobehavioral deficits, and seizures. Lethality was noted in 17% of Group 6 animals. In summary, preservation of AChE with a centrally active carbamate (PHY) pretreatment and MMB4 therapy appeared to offer the greatest degree of protection against lethality and development of seizures and neurobehavioral abnormalities.

Perinatal environmental tobacco smoke exposure in rhesus monkeys: critical periods and regional selectivity for effects on brain cell development and lipid peroxidation.

Perinatal environmental tobacco smoke (ETS) exposure in humans elicits neurobehavioral deficits. We exposed rhesus monkeys to ETS during gestation and through 13 months postnatally, or postnatally only (6–13 months). At the conclusion of exposure, we examined cerebrocortical regions and the midbrain for cell damage markers and lipid peroxidation. For perinatal ETS, two archetypal patterns were seen in the various regions, one characterized by cell loss (reduced DNA concentration) and corresponding increases in cell size (increased protein/DNA ratio), and a second pattern suggesting replacement of larger neuronal cells with smaller and more numerous glia (increased DNA concentration, decreased protein/DNA ratio). The membrane/total protein ratio, a biomarker of neurite formation, also indicated potential damage to neuronal projections, accompanied by reactive sprouting. When ETS exposure was restricted to the postnatal period, the effects were similar in regional selectivity, direction, and magnitude. These patterns resemble the effects of prenatal nicotine exposure in rodent and primate models. Surprisingly, perinatal ETS exposure reduced the level of lipid peroxidation as assessed by the concentration of thiobarbituric acid reactive species, whereas postnatal ETS did not. The heart, a tissue that, like the brain, has high oxygen demand, displayed a similar but earlier decrease (2–3 months) in lipid peroxidation in the perinatal exposure model, whereas values were reduced at 13 months with the postnatal exposure paradigm. Our results provide a mechanistic connection between perinatal ETS exposure and neurobehavioral anomalies, reinforce the role of nicotine in these effects, and buttress the importance of restricting or eliminating ETS exposure in young children.

Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a.

The human UBE3A gene shows brain-specific partial imprinting, and lack of a maternally inherited allele causes Angelman syndrome (AS), which is characterized by neurobehavioral anomalies. In several AS model mice, imprinted Ube3a expression is detected predominantly in the hippocampus, cerebellar Purkinje cells and the olfactory bulb. Therefore, imprinting of mouse Ube3a is thought to be region-specific with different levels of silencing of the paternal Ube3a allele in different brain regions. To determine cell types of imprinted Ube3a expression, we analyzed its imprinting status in embryonic brain cells by using primary cortical cell cultures. RT-PCR and immunofluorescence were performed to determine the allelic expression of the gene. The Ube3a gene encodes two RNA transcripts in the brain, sense and antisense. The sense transcript was expressed maternally in neurons but biallelically in glial cells in the embryonic brain, whereas the antisense transcript was expressed only in neurons and only from the paternal allele. Our data present evidence of brain cell type-specific imprinting, i.e. neuron-specific imprinting of Ube3a in primary brain cell cultures. Reciprocal imprinting of sense and antisense transcripts present only in neurons suggests that the neuron-specific imprinting mechanism is related to the lineage determination of neural stem cells.

A novel maternally expressed gene, ATP10C, encodes a putative aminophospholipid translocase associated with Angelman syndrome.

Lack of a maternal contribution to the genome at the imprinted domain on proximal chromosome 15 causes Angelman syndrome (AS) associated with neurobehavioral anomalies that include severe mental retardation, ataxia and epilepsy. Although AS patients have infrequent mutations in the gene encoding an E6-AP ubiquitin ligase required for long-term synaptic potentiation (LTP), most cases are attributed to de novo maternal deletions of 15q11-q13. We report here that a novel maternally expressed gene, ATP10C, maps within the most common interval of deletion and that ATP10C expression is virtually absent from AS patients with imprinting mutations, as well as from patients with maternal deletions of 15q11-q13.

A review of the neurobehavioral deficits in children with fetal alcohol syndrome or prenatal exposure to alcohol.

Fetal alcohol syndrome is a devastating developmental disorder caused by prenatal exposure to high amounts of alcohol. In addition to structural abnormalities and growth deficits, fetal alcohol syndrome is associated with a broad spectrum of neurobehavioral anomalies. This paper reviews the behavioral and cognitive effects of prenatal alcohol exposure. More than 20 years of research are discussed, with a focus on IQ, activity, attention, learning, memory, language, motor, and visuospatial abilities in children prenatally exposed to varying amounts of alcohol, including those with fetal alcohol syndrome.