Postnatal nutritional iron deficiency impairs dopaminergic-mediated synaptic plasticity in the CA1 area of the hippocampus.

OBJECTIVES: Developmental iron deficiency (ID) has been shown to put children at risk for compromised learning and memory capacity, and it has also been shown to impair hippocampus-dependent forms of memory as well as hippocampal synaptic transmission. Catecholamines are known to play a pivotal role in memory consolidation, and studies have demonstrated that perinatal ID alters dopaminergic systems in various brain areas. It is not known, however, whether perinatal ID impairs dopaminergic synaptic plasticity in learning and memory structures such as the hippocampus. The objective of the present study was to examine dopaminergic-mediated synaptic efficacy in the hippocampus of mice subjected to an ID or control (CN) diet. METHODS: The present study used electrophysiological brain slice methods to examine dopaminergic-mediated synaptic efficacy in the hippocampus of mice subjected to an ID or CN diet from postnatal day (P) P0 through P20. Hippocampal brain slices were prepared in young (P26-30) and adult animals (P60-64). Synaptic efficacy was measured in CA1 neurons by examining population spike amplitude. Slices were treated with the dopaminergic agonist SKF-38393. RESULTS: Slices obtained from young and adult CN mice exhibited a long-lasting increase in synaptic efficacy as the result of SKF-38393 perfusion while the young and adult ID slices showed little or no increase. DISCUSSION: The present study demonstrates that postnatal ID produces long-lasting impairments in dopaminergic-dependent synaptic plasticity in the hippocampus. These impairments may play a role in the learning and memory deficits known to result from ID.

Anticoagulant effects of low-molecular-weight heparins in healthy cats.

BACKGROUND: Low-molecular-weight heparin (LMWH) has potential benefit in cats at risk for thromboembolic disease. However, LMWH pharmacokinetics has not been characterized in the cat. Drug effect with LMWH may be evaluated with analysis of factor Xa inhibition (anti-Xa) or thromboelastography (TEG). HYPOTHESIS: Administration of LMWH at previously recommended dosages and schedules to healthy cats will result in inhibition of factor Xa and hypocoagulable TEG. ANIMALS: In vivo research with heparin was performed in 5 purpose-bred cats. METHODS: In a prospective study with randomized crossover design, heparin or placebo was administered. Treatments were unfractionated heparin (UFH), 250 IU/kg q6h; dalteparin, 100 IU/kg q12h; enoxaparin, 1 mg/kg q12h; or 0.9% saline, 0.25 mL/kg q6h. Each drug was administered for 5 consecutive days followed by a minimum washout of 14 days. Baseline and post-treatment analyses included anti-Xa, TEG, and prothrombin time/activated partial thromboplastin time. RESULTS: Mean anti-Xa activity 4 hours after enoxaparin (0.48 U/mL) approached the human therapeutic target (0.5-1.0 U/mL); however, mean trough anti-Xa activity was below detection limits. Mean anti-Xa activity 4 hours after dalteparin was lower, and only 1 cat attained therapeutic target at a single time point. Cats receiving UFH attained target anti-Xa activity and changes in TEG at trough and 4 hours. CONCLUSIONS: Cats have rapid absorption and elimination kinetics with LMWH therapy. On the basis of pharmacokinetic modeling, cats will require higher dosages and more frequent administration of LMWH to achieve human therapeutic anti-factor Xa activity of 0.5-1 U/mL. Peak anti-Xa activity is predicted at 2 hours after administration of LMWH.

Amyloid Precursor Protein Haploinsufficiency Preferentially Mediates Brain Iron Accumulation in Mice Transgenic for The Huntington's Disease Mutation.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant disorder caused by a CAG expansion in the huntingtin gene that results in expression of mutant huntingtin protein. Iron accumulates in HD brain neurons. Amyloid precursor protein (APP) promotes neuronal iron export. However, the role of APP in brain iron accumulation in HD is unclear. OBJECTIVE: To determine the effects of APP insufficiency on HD in YAC128 mice. METHODS: We crossed APP hemizygous mice (APP+/-) with YAC128 mice that are transgenic (Tg) for human mutant huntingtin (hmHTT) to generate APP+/+ hmHTT-/-, APP+/- hmHTT-/-, APP+/+ hmHTT+/- and APP+/- hmHTT+/- progeny. Mice were evaluated for behavioral, biochemical and neuropathology HD outcomes at 2-12 months of age. RESULTS: APP heterozygosity decreased cortical APP 25% and 60% in non-Tg and Tg mice, respectively. Cerebral and striatal iron levels were increased by APP knockdown in Tg mice only. Nest-building behavior was decreased in Tg mice; APP knockdown decreased nest building in non-Tg but not Tg mice. Rota-rod endurance was decreased in Tg mice. APP+/- hHTT+/- mice demonstrated additional decreases in rota-rod endurance from 4-10 months of age. Tg mice had smaller striatal volumes and fewer striatal neurons but were not affected by APP knockdown. CONCLUSIONS: APP heterozygosity results in greater decreases of cortical APP in Tg versus non-Tg mice. Mutant huntingtin transgenic mice develop brain iron accumulation as a result of greater suppression of APP levels. Elevated brain iron in Tg mice was associated with a decline in motor endurance consistent with a disease promoting effect of iron in the YAC128 model of human HD.

Neonatal Iron Supplementation Induces Striatal Atrophy in Female YAC128 Huntington's Disease Mice.

BACKGROUND: Dysregulation of iron homeostasis is implicated in the pathogenesis of Huntington's disease. We have previously shown that increased iron intake in R6/2 HD neonatal mice, but not adult R6/2 HD mice potentiates disease outcomes at 12-weeks of age corresponding to advanced HD [Redox Biol. 2015;4 : 363-74]. However, whether these findings extend to other HD models is unknown. In particular, it is unclear if increased neonatal iron intake can promote neurodegeneration in mouse HD models where disease onset is delayed to mid-adult life. OBJECTIVE: To determine if increased dietary iron intake in neonatal and adult life-stages potentiates HD in the slowly progressive YAC128 HD mouse model. METHODS: Female neonatal mice were supplemented daily from days 10-17 with 120µg/g body weight of carbonyl iron. Adult mice were provided diets containing low (50 ppm), medium (150 ppm) and high (500 ppm) iron concentrations from 2-months of age. HD progression was determined using behavioral, brain morphometric and biochemical approaches. RESULTS: Neonatal-iron supplemented YAC128 HD mice had significantly lower striatal volumes and striatal neuronal cell body volumes as compared to control HD mice at 1-year of age. Neonatal-iron supplementation of HD mice had no effect on rota-rod motor endurance and brain iron or glutathione status. Adult iron intake level had no effect on HD progression. YAC128 HD mice had altered peripheral responses to iron intake compared to iron-matched wild-type controls. CONCLUSIONS: Female YAC128 HD mice supplemented with nutritionally-relevant levels of iron as neonates demonstrate increased striatal degeneration 1-year later.