ABSTRACT
Although one of the defining characteristics of Alzheimer's disease is the presence of amyloid-beta (Aß) plaques, the early accumulation of soluble Aß oligomers (AßOs) may disrupt synaptic function and trigger cognitive impairments long before the appearance of plaques. Furthermore, murine models aimed at understanding how AßOs alter formation and retrieval of associative memories are conducted using human Aß species, which are more neurotoxic in the mouse brain than the native murine species. Unfortunately, there is currently a lack of attention in the literature as to what the murine version of the peptide (mAß) does to synaptic function and how it impacts the consolidation and retrieval of associative memories. In the current study, adult mice were infused with mAß 0, 2, 6, or 46â¯h after contextual-fear conditioning, and were tested 2-48â¯h later. Interestingly, only mAß infusions within 2â¯h of training reduced freezing behavior at test, indicating that mAß disrupted the consolidation, but not retrieval of fear memory. This consolidation deficit coincided with increased IL-1ß and reduced synaptophysin mRNA levels, without disrupting other synaptic signaling-related genes here examined. Despite differences between murine and human Aß, the deleterious functional outcomes of early-stage synaptic oligomer presence are similar. Thus, models utilizing or inducing the production of mAß in non-transgenic animals are useful in exploring the role of dysregulated synaptic plasticity and resultant learning deficits induced by Aß oligomers.
Subject(s)
Amyloid beta-Peptides/pharmacology , Behavior, Animal/drug effects , Conditioning, Classical/drug effects , Fear/drug effects , Hippocampus/drug effects , Inflammation/chemically induced , Memory Consolidation/drug effects , Mental Recall/drug effects , Alzheimer Disease/metabolism , Amyloid beta-Peptides/administration & dosage , Animals , Disease Models, Animal , Hippocampus/immunology , Hippocampus/metabolism , Inflammation/immunology , Inflammation/metabolism , Infusions, Intraventricular , Male , Mice , Mice, Inbred C57BLABSTRACT
Pregnant SWV mice were treated on day 9 of gestation (PC) with 50 mg/kg of caffeine (CAFF), 200 mg/kg (LD) or 1000 mg/kg (HD) of acetazolamide (ACZM), or a combination of both agents, or on day 8 PC with both agents (ACZM + CAFF). Untreated (UNTD) and vehicle-treated (VEH) groups served as controls. The SWV strain is widely reported to be resistant to ACZM; it was resistant to ACZM or CAFF + ACZM when treated on day 9 of gestation, but a significant frequency of malformations, primarily exencephaly, was produced by ACZM + CAFF on day 8 PC. This study provides evidence that ACZM, coupled with a subteratogenic dose of caffeine can produce abnormalities in the "resistant" SWV mice, using the endpoint of exencephaly on day 8 of gestation. The mean number of ossified caudal vertebrae in day-9 treatments and ossified cervical vertebral centra in day-8 treatments were reduced. The frequency of ossification of the first cervical vertebra (C1) was reduced from 93% in UNTD to 39% in HD-ACZM day 9 PC and 69% in HD-ACZM + CAFF day 9 PC groups, and was also significantly reduced in the HD-ACZM + CAFF day-8 treated group.
Subject(s)
Acetazolamide/toxicity , Brain/abnormalities , Caffeine/toxicity , Animals , Birth Weight/drug effects , Cervical Vertebrae/abnormalities , Embryo, Mammalian/drug effects , Female , Fetal Death/chemically induced , Litter Size/drug effects , Mice , Mice, Inbred Strains , Osteogenesis/drug effects , PregnancyABSTRACT
Pregnant C57BL/6J mice were treated with 0 or 50 mg of caffeine (CAFF) per kg, and 0, 200 mg/kg (L) or 1,000 mg/kg (H) of acetazolamide (ACZM) during day 9 of gestation (9DPC). Individual fetuses were examined for gross morphological abnormalities and skeletal variations. The increase in fetal malformations seen, especially right forelimb electrodactyly, was augmented at both dose levels of acetazolamide by concomitant exposure to caffeine. Both frequency and severity of ectrodactyly were potentiated by caffeine. Skeletal examination revealed a reduction of the number of ossified cervical and caudal vertebral centra among litters exposed to ACZM at either dose. In either case (ACZM-H, ACZM-L) that effect was augmented by co-administration of CAFF. The first cervical vertebra (C1) appeared to provide the most sensitive index of teratogenic exposure. This study provides evidence that a subteratogenic dose of caffeine can potentiate the teratogenic effect of acetazolamide in C57BL/6J mice when dams are treated on day 9 of gestation. In addition, skeletal examination provided evidence that simultaneous treatment with both agents delayed fetal development. Many litters exposed to ACZM or both agents displayed a reduction in skeletal ossification even in the absence of gross morphological abnormalities, suggesting that ossification can be used as an indicator of prenatal exposure to potentially harmful substances in the C57BL/6 mouse strain.
