Arsenic transformations in terrestrial small mammal food chains from contaminated sites in Canada.

Arsenic in terrestrial contaminated sites has the potential to cause harm to residential wildlife. The aim of this study was to determine the arsenic species in wild rodents living in arsenic contaminated habitats, specifically deer mice from Yellowknife, NT and meadow voles from Seal Harbour, NS, along with co-located plants. Methanol : water (1 : 1) extractions were used to optimize the extraction of methylated arsenic(v) species. Total arsenic concentrations were substantially higher in the Yellowknife deer mice (1.7-3.2 µg kg(-1) wet weight in livers) and Seal Harbour meadow voles (0.67-0.97 µg kg(-1) wet weight in livers) living on the contaminated sites with respect to the surrounding background locations (0.12-0.34 µg kg(-1) wet weight in livers). Around 50% of arsenic could be identified in Yellowknife deer mouse tissues, but only <10% was identified in Seal Harbour vole tissues; inorganic arsenic (iii and v) and dimethylarsinic acid were all found. Monomethylarsonic acid was only detected in both the mice and voles living in the contaminated sites. In the Yellowknife food chain, methyl arsenic (v) proportions increased from plants to mouse inner organs, but the trend was not for clear as the Seal Harbour food chain. Seal Harbour voles may be sequestering arsenic in a less mobile form, rather than transforming it.

A guide to the genetics of psychiatric disease.

The road to scientific discovery begins with an awareness of what is unknown. Research in science can in some ways be like putting together the pieces of a puzzle without having the benefit of the box-top picture of the completed puzzle. The "picture" in science is an understanding of how nature works in a particular instance, and it takes many separate pieces of the "puzzle" to put this understanding together. These pieces are always of different kinds of data, often obtained using different approaches and techniques. The challenge of the researcher is to picture or hypothesize each of the missing pieces before actually having them in hand, so they can be sought and tested in the laboratory. This "picturing" is actually having a clear idea of what you don't know: having a clear image of the "shape" of the missing piece. This is easy when the puzzle surrounding the missing piece is already in hand, but more difficult with less of it constrained by what is already known. In putting paper puzzles together, the shape of the pieces is not the only limitation that needs to be satisfied. There is also the picture to satisfy, that is, the picture usually has to make sense. In science these constraints can be manifold, and usually the quality of the research is judged by the number of ways a piece of data integrates into and brings together the rest of the puzzle. The multidimensionality of scientific questions makes it virtually essential that as many different pieces of the puzzle as possible be obtained. The more that is not known about the puzzle, the more pieces you need. Thus it is with the genetics of psychiatric diseases. In this guide, we will explore as many of the domains of the genetic puzzle as we are aware of. We will learn a bit of the language of each and how they fit into the puzzle with at least one anecdote to serve as an example. Mapping unknown territory is always a process, but we hope this guide will increase the reader's awareness of what is unknown.

Identification of gene markers based on well validated and subcategorized stressed animals for potential clinical applications in PTSD.

Post-traumatic stress disorder (PTSD) is a complex mental disorder that can develop in response to traumatic experiences. The molecular mechanisms underlying the pathology of PTSD are poorly understood, and this lack of knowledge hampers our ability to find superior therapeutic approaches to the treatment of this disorder. There are two main reasons for our lack of study in this area: here is no sufficiently validated animal model and lack of large-scale studies for the search of underlying molecular mechanisms. Thus, to promote research on PTSD (especially its molecular mechanisms) and to set molecular basis for searching novel medications of this disorder, large-scale, genome-wide interrogation of a significant amount of genes based upon a well validated animal model is demanded. We hypothesize that a significant number of genes are involved in PTSD. It is only with a large number of these genes identified in specific samples of PTSD-related population, and then it is possible for a sufficient understanding of the pathology at the molecular level of a PTSD, as well as for enhancing the PTSD's therapeutic and preventative strategies. Two prerequisites are needed for testing this hypothesis: (1) relative pure samples from a well validated animal model; and (2) genome-wide screening of PTSD molecular targets. For the animal model, we suggest to use the predator-exposure paradigm, in which rats are exposed to a predator, this model has previously been evaluated behaviorally well emulated the clinical symptoms of PTSD. For a better stringency, three criteria can be used to further validate this animal model: analogous (similarity of behavior), predictive (predictability of drug response) and biological mechanism (e.g., electrophysiological and pathological change in amygdala). For large-scale molecular target screening, the new microarray technology, which can profile expression of tens of thousands genes simultaneously, is the method of choice. The validity and practicability of this hypothesis and the strategy for its testing have been supported by our preliminary laboratory data.

The paradoxical effects of SKF83959, a novel dopamine D1-like receptor agonist, in the rat acoustic startle reflex paradigm.

While the benzazepine SKF83959 elicits classical behavioral responses associated with dopamine D1 receptors, it also acts as a D1 receptor antagonist biochemically. The paradoxical properties of this agent remain an enigma. In the present study, we sought to determine the behavioral effects of SKF83959 in the rat acoustic startle reflex test. Systemic administration of SKF83959 produced a dose-related increase in the startle amplitude with a stimulus of 105 dB, and a significant group difference was observed between animals treated with 1 mg/kg SKF83959 and vehicle controls. SKF83959 also significantly reduced the latency to startle response to stimuli of 95 dB and 105 dB in a dose-dependent manner. However, unlike classical dopamine D1-like receptor agonists, SKF83959 failed to disrupt prepulse inhibition (PPI) of either the startle amplitude or the latency to startle response; rather, the agent dose-dependently increased the PPI latency to startle response of 105 dB stimulus. These results suggest that the behavioral effects of SKF83959 in the rat acoustic startle reflex paradigm are paradoxical, and these paradoxical effects may be associated with its distinct pharmacological properties.

Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases.

Increasing evidence supports the notion that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a protein with multiple functions, including its surprising role in apoptosis. GAPDH is overexpressed and accumulates in the nucleus during apoptosis induced by a variety of insults in diverse cell types. Knockdown of GAPDH using an antisense strategy demonstrates its involvement in the apoptotic cascade in which GAPDH nuclear translocation appears essential. Knowledge concerning the mechanisms underlying GAPDH nuclear translocation and subsequent cell death is growing. Additional evidence suggests that GAPDH may be an intracellular sensor of oxidative stress during early apoptosis. Abnormal expression, nuclear accumulation, changes in physical properties, and loss of glycolytic activity of GAPDH have been found in cellular and transgenic models as well as postmortem tissues of several neurodegenerative diseases. The interaction of GAPDH with disease-related proteins as well as drugs used to treat these diseases suggests that it is a potential molecular target for drug development.

The mitochondrial toxin, 3-nitropropionic acid, induces extracellular Zn2+ accumulation in rat hippocampus slices.

3-nitropropionic acid (3-NPA), a suicide inhibitor of succinate dehydrogenase (SDH; complex II), has been used to provide useful experimental models of Huntington's disease (HD) and "chemical hypoxia" in rodents. The trace ion Zn2+ has been shown to cause neurodegeneration. Employing real-time Newport Green fluorescence imaging of extracellular Zn2+, we found that 3-NPA (10-100 microM) caused a concentration-dependent increase in the concentration of extracellular Zn2+ ([Zn2+]o) in acute rat hippocampus slices. This increase in [Zn2+]o was abolished by 10 mM CaEDTA. The increase of [Zn2+]o was also accompanied by a rapid increase of cytoplasmic-free Zn2+ concentration ([Zn2+]i). The induction of Zn2+ release by 3-MPA in hippocampus slices points to a potential mechanism by which 3-NPA might induce neurodegeneration.

Stress impairs alpha(1A) adrenoceptor-mediated noradrenergic facilitation of GABAergic transmission in the basolateral amygdala.

Intense or chronic stress can produce pathophysiological alterations in the systems involved in the stress response. The amygdala is a key component of the brain's neuronal network that processes and assigns emotional value to life's experiences, consolidates the memory of emotionally significant events, and organizes the behavioral response to these events. Clinical evidence indicates that certain stress-related affective disorders are associated with changes in the amygdala's excitability, implicating a possible dysfunction of the GABAergic system. An important modulator of the GABAergic synaptic transmission, and one that is also central to the stress response is norepinephrine (NE). In the present study, we examined the hypothesis that stress impairs the noradrenergic modulation of GABAergic transmission in the basolateral amygdala (BLA). In control rats, NE (10 microM) facilitated spontaneous, evoked, and miniature IPSCs in the presence of beta and alpha(2) adrenoceptor antagonists. The effects of NE were not blocked by alpha(1D) and alpha(1B) adrenoceptor antagonists, and were mimicked by the alpha(1A) agonist, A61603 (1 microM). In restrain/tail-shock stressed rats, NE or A61603 had no significant effects on GABAergic transmission. Thus, in the BLA, NE acting via presynaptic alpha(1A) adrenoceptors facilitates GABAergic inhibition, and this effect is severely impaired by stress. This is the first direct evidence of stress-induced impairment in the modulation of GABAergic synaptic transmission. The present findings provide an insight into possible mechanisms underlying the antiepileptogenic effects of NE in temporal lobe epilepsy, the hyperexcitability and hyper-responsiveness of the amygdala in certain stress-related affective disorders, and the stress-induced exacerbation of seizure activity in epileptic patients.

Neurobiology of bipolar illness: implications for future study and therapeutics.

Many findings implicating prefrontal cortical and limbic areas of the brain and endocrine systems in the neuropathology and pathophysiology of bipolar illness have greatly increased our understanding of the neurobiology of the illness. New imaging techniques such as PET, MRI, SPECT, and MRS have detailed more evidence of specific regional alterations in the brains of bipolar patients than was thought possible just 20 years ago. These methods are beginning to be used to help predict response to treatment. Examining the mechanisms of action of mood stabilizers (such as lithium, carbamazepine, and valproate) has provided clues to potential underlying neurobiological abnormalities in the illness. Recent studies of postmortem brain tissue have begun to confirm prefrontal cortical and limbic neurochemical and microstructural alterations in patients with bipolar illness compared with controls. It is postulated that it is the balance between primary pathological versus secondary adaptive alterations in gene expression in the illness and their enhancement or dampening by pharmacotherapy, that may determine the episodic course of mood fluctuations and remissions. Further examination of the pathophysiology and neurobiology of bipolar illness should lead to both more effective treatments and, potentially, secondary and even primary episode prevention.

Do we need zinc to think?

Chelatable Zn(2+), which is found in the synaptic vesicles of certain glutamatergic neurons in several regions of the forebrain, is released during neuronal activity. Zn(2+) exhibits numerous effects on ligand-gated and voltage-dependent ion channels, and released Zn(2+) is therefore likely able to modulate synaptic transmission. The physiologically relevant actions of Zn(2+), however, have remained unclear. Recent research exploiting improved Zn(2+)-sensitive optical probes has suggested some intriguing effects for synaptically released Zn(2+), including heterosynaptic regulation of N-methyl-D-aspartate (NMDA) receptor function, and a novel role as a trans-synaptic second messenger that may enter postsynaptic neurons to modulate various signal transduction pathways.

Neuroprotective effects of lithium in cultured cells and animal models of diseases.

Lithium, the major drug used to treat manic depressive illness, robustly protects cultured rat brain neurons from glutamate excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors. The lithium neuroprotection against glutamate excitotoxiciy is long-lasting, requires long-term pretreatment and occurs at therapeutic concentrations of this drug. The neuroprotective mcchanisms involve inactivation of NMDA receptors, decreased expression of pro-apoptotic proteins, p53 and Bax, enhanced expression of the cytoprotective protein, Bcl-2, and activation of the cell survival kinase, Akt. In addition, lithium pretreatment suppresses glutamate-induced loss of the activities of Akt, cyclic AMP-response element binding protein (CREB), c-Jun - N-terminal kinase (JNK) and p38 kinase. Lithium also reduces brain damage in animal models of neurodegenerative diseases in which excitotoxicity has been implicated. In the rat model of stroke using middle cerebral artery occlusion, lithium markedly reduces neurologic deficits and decreases brain infarct volume even when administered after the onset of ischemia. In a rat Huntington's disease model, lithium significantly reduces brain lesions resulting from intrastriatal infusion of quinolinic acid, an excitotoxin. Our results suggest that lithium might have utility in the treatment of neurodegenerative disorders in addition to its common use for the treatment of bipolar depressive patients.

Decreased prefrontal CaMKII alpha mRNA in bipolar illness.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays critical roles in neurotransmission, synaptic plasticity, learning and memory. The aim of this study was to examine, by in situ hybridization, prefrontal cortical expression of CaMKII alpha mRNA in postmortem brains of unipolar, bipolar, schizophrenic, and control subjects. Compared to controls, bipolar patients had significantly lower levels of CaMKII alpha mRNA in laminae I-VI of Brodmann's area 9 and laminae I-III and VI of area 46. Unipolar patients also exhibited significantly lower levels of CaMKII alpha mRNA in laminae I-IV of area 9 than did controls. The significant decrease in CaMKII alpha mRNA in bipolar patients could be associated with some of the affective and cognitive alterations that have been linked to prefrontal cortical dysfunction in bipolar disorder, although this requires further direct examination.

Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation.

The therapeutic mechanisms of lithium for treating bipolar mood disorder remain poorly understood. Recent studies demonstrate that lithium has neuroprotective actions against a variety of insults. Here, we studied neuroprotective effects of lithium against excitotoxicity in cultured cerebral cortical neurons. Glutamate-induced excitotoxicity in cortical neurons was exclusively mediated by NMDA receptors. Pre-treatment of cortical neurons with LiCl time-dependently suppressed excitotoxicity with maximal protection after 6 days of pre-treatment. Significant protection was observed at the therapeutic and subtherapeutic concentration of 0.2-1.6 mm LiCl with almost complete protection at 1 mM. Neuroprotection was also elicited by valproate, another major mood-stabilizer. The neuroprotective effects of lithium coincided with inhibition of NMDA receptor-mediated calcium influx. Lithium pre-treatment did not alter total protein levels of NR1, NR2A and NR2B subunits of NMDA receptors. However, it did markedly reduce the level of NR2B phosphorylation at Tyr1472 and this was temporally associated with its neuroprotective effect. Because NR2B tyrosine phosphorylation has been positively correlated with NMDA receptor-mediated synaptic activity and excitotoxicity, the suppression of NR2B phosphorylation by lithium is likely to result in the inactivation of NMDA receptors and contributes to neuroprotection against excitotoxicity. This action could also be relevant to its clinical efficacy for bipolar patients.