Passive avoidance learning and memory of 56Fe sham-irradiated and irradiated human apoE transgenic mice

Cranial irradiation is associated with long-term cognitive impairments, including deficits in hippocampus-dependent learning and memory. Not all people exposed to cranial radiation develop cognitive injury, suggesting the involvement of genetic risk factors. There may also be sex differences in susceptibility to develop radiation-induced cognitive injury. The three major human apolipoprotein E (apoE) isoforms are encoded by distinct alleles (epsilon2, epsilon3, and epsilon4). Compared with epsilon3, epsilon4 increases the risk of cognitive impairments following various challenges while epsilon2 provides relative protection. Women are at higher risk to develop Alzheimer's disease (AD) than men, particularly those carrying epsilon4. In previous experiments using male and female mice expressing human apoE-isoforms E2, E3 or E4 under the mouse apoE promoter, we showed that cranial irradiation with 137Cs (10 Gy) results in hippocampus-dependent cognitive impairments that are sex- and apoE-isoform dependent. 137Cs is a form of irradiation often used in the clinical setting. To investigate whether 56Fe irradiation also has sex- and apoE-isoform dependent effects on hippocampus-dependent cognitive function in human apoE mice, we sham-irradiated and irradiated 2-month old male and female human apoE mice at 3 Gy and assessed their performance in a passive avoidance learning and memory test three to five months later.     

Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy

Ion channel mutations are an important cause of rare Mendelian disorders affecting brain, heart, and other tissues. We performed parallel exome sequencing of 237 channel genes in a well-characterized human sample, comparing variant profiles of unaffected individuals to those with the most common neuronal excitability disorder, sporadic idiopathic epilepsy. Rare missense variation in known Mendelian disease genes is prevalent in both groups at similar complexity, revealing that even deleterious ion channel mutations confer uncertain risk to an individual depending on the other variants with which they are combined. Our findings indicate that variant discovery via large scale sequencing efforts is only a first step in illuminating the complex allelic architecture underlying personal disease risk. We propose that in?silico modeling of channel variation in realistic cell and network models will be crucial to future strategies assessing mutation profile pathogenicity and drug response in individuals with a broad spectrum of excitability disorders.     

TaqMan DNA technology confirms likely overestimation of cod (Gadus morhua L.) egg abundance in the Irish Sea: implications for the assessment of the cod stock and mapping of spawning areas using egg-based methods

Recent substantial declines in northeastern Atlantic cod stocks necessitate improved biological knowledge and the development of techniques to complement standard stock assessment methods (which largely depend on accurate commercial catch data). In 2003, an ichthyoplankton survey was undertaken in the Irish Sea and subsamples of 'cod-like' eggs were analysed using a TaqMan multiplex, PCR (polymerase chain reaction) assay (with specific probes for cod, haddock and whiting). The TaqMan method was readily applied to the large number of samples (n = 2770) generated during the survey and when combined with a manual DNA extraction protocol had a low failure rate of 6%. Of the early stage 'cod-like' eggs (1.2-1.75 mm diameter) positively identified: 34% were cod, 8% haddock and 58% whiting. As previous stock estimates based on egg surveys for Irish Sea cod assumed that the majority of 'cod-like' eggs were from cod, the TaqMan results confirm that there was probably substantial contamination by eggs of whiting and haddock that would have inflated estimates of the stock biomass.     

Sex- and APOE isoform-dependent effects of radiation on cognitive function

Clinical irradiation of the brain induces hippocampus-dependent cognitive impairments in some but not all individuals, suggesting the involvement of genetic risk factors. Deficiency of apolipoprotein E (APOE), which is important for the metabolism and redistribution of lipoproteins and cholesterol, increases behavioral impairments after irradiation, supporting a protective role for APOE against radiation-induced cognitive injury. Compared to APOE3, APOE4 increases while APOE2 decreases the risk of developing age-related cognitive decline and Alzheimer's disease, particularly in women. To determine the potential effects of APOE isoform and sex on radiation-induced cognitive impairments, we irradiated 2-month-old male and female APOE2, APOE3 and APOE4 mice and assessed their cognitive performance 3 months later. When hippocampus-dependent spatial learning and memory were assessed in the water maze, sham-irradiated female APOE2, APOE3 and APOE4 and irradiated female APOE2 mice showed spatial memory retention, but irradiated female APOE3 and APOE4 mice did not. Compared to sham-irradiated female APOE4 mice, irradiated female APOE4 mice also required more trials to reach criterion in the hippocampus-dependent passive avoidance test. Radiation had no effects on water maze or passive avoidance learning and memory of male APOE2, APOE3 or APOE4 mice, indicating that the effects of radiation on cognitive performance are dependent on sex- and APOE isoform.     

Evaluation of Toxicity of <Emphasis Type="Italic">Cercospora piaropi</Emphasis> in a Mycoherbicide Formulation by Using Bacterial Bioluminescence and the Ames Mutagenicity Tests

An evaluation of the potential hazards associated with mutagenicity and acute toxicity of a mycoherbicide formulation based on the fungal pathogen Cercospora piaropi was performed. Neither the mycoherbicide nor any of its components were mutagenic to Salmonella typhimurium TA98 and TA100 with or without metabolic activation. Both the C. piaropi and the mycoherbicide formulation were shown to be moderately toxic with a bacterial bioluminescence assay. No acute toxicity was found in water samples taken from tanks after treatment of water hyacinth with the mycoherbicide.     

Effects of ⁵⁶Fe-particle cranial radiation on hippocampus-dependent cognition depend on the salience of the environmental stimuli

Ionizing radiation reduces the numbers of neurons expressing activity-regulated cytoskeleton-associated protein (Arc) in the hippocampal dentate gyrus (DG). It is currently unclear if that change relates to cognitive function. We assessed the effects of 1 Gy of head-only ??Fe-particle irradiation on hippocampus-dependent and hippocampus-independent fear conditioning and determined how those changes related to Arc expression within the DG. Irradiated mice that did not receive tone-shock pairings on day 1 showed less freezing in the same context on a second day and a lower fraction of Arc-expressing neurons in the free (lower) blade of the DG than sham-irradiated mice. Those data suggested reduced hippocampus-dependent spatial habituation learning. Changes in Arc expression in the free blade correlated positively with freezing in mice that did not receive tone-shock pairings. However, irradiated mice that did receive tone-shock pairings showed enhanced contextual freezing but a reduced percentage of Arc-expressing neurons in the enclosed (upper) blade. Changes in Arc expression correlated negatively with freezing in mice that received tone-shock pairings. In animals receiving cued fear conditioning, radiation did not affect cognitive performance or the fractions of Arc-expressing neurons. While the relationship between Arc expression and cognitive performance is complex, our data suggest that radiation effects on hippocampus-dependent cognition might depend on the prominence (salience) of environmental stimuli and blade-specific Arc expression.     

NMDA receptor activation induces translocation and activation of Rac in mouse hippocampal area CA1

Neuronal development requires several discrete morphological steps that are believed to involve the small GTPase Rac. For example, neural activity, through NMDA receptors and/or AMPA receptors, activates Rac leading to elaboration of dendritic arbors. In the current study, we have conducted studies which indicate that Rac might be an important molecule involved in morphological plasticity in the adult mouse. We demonstrate that Rac is expressed at synapses in the adult mouse hippocampus. We also demonstrate that treatment of hippocampal slices with NMDA induces membrane translocation and activation of Rac in area CA1. Interestingly, we also find that there is an increase in Rac that is associated with NMDA receptor complexes following NMDA receptor activation. Taken together, our data are consistent with the idea that Rac could be participating in NMDA receptor-dependent changes in morphology that occur during synaptic plasticity and memory formation in the adult mouse hippocampus.     

Isoform-dependent effects of apoE on doublecortin-positive cells and microtubule-associated protein 2 immunoreactivity following 137Cs irradiation

Previously we found apoE isoform-dependent effects of ¹³⁷Cs irradiation on cognitive function of female mice 3 months following irradiation. Alterations in the number of immature neurons and in the levels of the dendritic marker microtubule-associated protein 2 (MAP-2) might contribute to the cognitive changes following irradiation. Therefore, in the present study we determined if, following ¹³⁷Cs irradiation, there are apoE isoform-dependent effects on loss of doublecortin-positive neuroprogenitor cells or MAP-2 immumonoreactivity. In the dentate gyrus, CA1 and CA3 regions of the hippocampus, enthorhinal and sensorimotor cortex, and central and basolateral nuclei of the amygdala of apoE3 female mice, MAP-2 immunoreactivity increased 3 months following ¹³⁷Cs irradiation. In addition, at 8 h following irradiation, the number of doublecortin-positive cells was higher in apoE3 than apoE2 or apoE4 mice. Together, these data indicate that brains of apoE3 mice respond differently to ¹³⁷Cs irradiation than those of apoE2 or apoE4 mice.