The neurotoxicology of uranium Dinocourt, Céline; Legrand, Marie; Dublineau, Isabelle ...
Toxicology (Amsterdam),
11/2015, Letnik:
337
Journal Article
Recenzirano
Odprti dostop
Abstract The brain is a target of environmental toxic pollutants that impair cerebral functions. Uranium is present in the environment as a result of natural deposits and release by human ...applications. The first part of this review describes the passage of uranium into the brain, and its effects on neurological functions and cognitive abilities. Very few human studies have looked at its cognitive effects. Experimental studies show that after exposure, uranium can reach the brain and lead to neurobehavioral impairments, including increased locomotor activity, perturbation of the sleep-wake cycle, decreased memory, and increased anxiety. The mechanisms underlying these neurobehavioral disturbances are not clearly understood. It is evident that there must be more than one toxic mechanism and that it might include different targets in the brain. In the second part, we therefore review the principal mechanisms that have been investigated in experimental models: imbalance of the anti/pro-oxidant system and neurochemical and neurophysiological pathways. Uranium effects are clearly specific according to brain area, dose, and time. Nonetheless, this review demonstrates the paucity of data about its effects on developmental processes and the need for more attention to the consequences of exposure during development.
Glickfeld and colleagues (2009) suggested that single hippocampal interneurones generate field potentials at monosynaptic latencies. We pursued this obervation in simultaneous intracellular and ...multiple extracellular records from the CA3 region of rat hippocampal slices. We confirmed that interneurones evoked field potentials at monosynaptic latencies. Pyramidal cells initiated disynaptic inhibitory field potentials, but did not initiate detectable monosynaptic excitatory fields. We confirmed that inhibitory fields were GABAergic in nature and showed they were suppressed at low external Cl−, suggesting they originate at postsynaptic sites. Field potentials generated by a single interneurone were detected at multiple sites over distances of more than 800 μm along the stratum pyramidale of the CA3 region. We used arrays of extracellular electrodes to examine amplitude distributions of spontaneous inhibitory fields recorded at sites orthogonal to or along the CA3 stratum pyramidale. Cluster analysis of spatially distributed inhibitory field events let us separate events generated by interneurones terminating on distinct zones of somato‐dendritic axis. Events generated at dendritic sites had similar amplitudes but occurred less frequently and had somewhat slower kinetics than perisomatic events generated near the stratum pyramidale. In records from multiple sites in the CA3 stratum pyramidale, we distinguished inhibitory fields that seemed to be initiated by interneurones with spatially distinct axonal arborisations.
Extracellular signals such as local field potentials and the EEG are used to measure brain activity. Here we show that single inhibitory cells of the hippocampus can generate field potentials. These signals probably depend on the number and high density of synapses made by a single neurone. Multiple extracellular records made with electrodes placed in different orientations let us distinguish non‐invasively the spontaneous activity of inhibitory cells that make different spatial patterns of synapses.
Mutations of the LGI1 (leucine-rich, glioma-inactivated 1) gene underlie autosomal dominant lateral temporal lobe epilepsy, a focal idiopathic inherited epilepsy syndrome. The LGI1 gene encodes a ...protein secreted by neurons, one of the only non-ion channel genes implicated in idiopathic familial epilepsy. While mutations probably result in a loss of function, the role of LGI1 in the pathophysiology of epilepsy remains unclear. Here we generated a germline knockout mouse for LGI1 and examined spontaneous seizure characteristics, changes in threshold for induced seizures and hippocampal pathology. Frequent spontaneous seizures emerged in homozygous LGI1−/− mice during the second postnatal week. Properties of these spontaneous events were examined in a simultaneous video and intracranial electroencephalographic recording. Their mean duration was 120 ± 12 s, and behavioural correlates consisted of an initial immobility, automatisms, sometimes followed by wild running and tonic and/or clonic movements. Electroencephalographic monitoring indicated that seizures originated earlier in the hippocampus than in the cortex. LGI1−/− mice did not survive beyond postnatal day 20, probably due to seizures and failure to feed. While no major developmental abnormalities were observed, after recurrent seizures we detected neuronal loss, mossy fibre sprouting, astrocyte reactivity and granule cell dispersion in the hippocampus of LGI1−/− mice. In contrast, heterozygous LGI1+/− littermates displayed no spontaneous behavioural epileptic seizures, but auditory stimuli induced seizures at a lower threshold, reflecting the human pathology of sound-triggered seizures in some patients. We conclude that LGI1+/− and LGI1−/− mice may provide useful models for lateral temporal lobe epilepsy, and more generally idiopathic focal epilepsy.
Uranium exposure leads to cerebral dysfunction involving for instance biochemical, neurochemical and neurobehavioral effects. Most studies have focused on mechanisms in uranium-exposed adult animals. ...However, recent data on developing animals have shown that the developing brain is also sensitive to uranium. Models of uranium exposure during brain development highlight the need to improve our understanding of the effects of uranium. In a model in which uranium exposure began from the first day of gestation, we studied the neurobehavioral consequences as well as the progression of hippocampal neurogenesis in animals from dams exposed to uranium. Our results show that 2-month-old rats exposed to uranium from gestational day 1 displayed deficits in special memory and a prominent depressive-like phenotype. Cell proliferation was not disturbed in these animals, as shown by 5-bromo-2'deoxyuridine (BrdU)/neuronal specific nuclear protein (NeuN) immunostaining in the dentate gyrus. However, in some animals, the pyramidal cell layer was dispersed in the CA3 region. From our previous results with the same model, the hypothesis of alterations of neurogenesis at prior stages of development is worth considering, but is probably not the only one. Therefore, further investigations are needed to correlate cerebral dysfunction and its underlying mechanistic pathways.
We report data on the neuronal form, synaptic connectivity, neuronal excitability and epileptiform population activities generated by the hippocampus of animals with an inactivated doublecortin gene. ...The protein product of this gene affects neuronal migration during development. Human doublecortin (DCX) mutations are associated with lissencephaly, subcortical band heterotopia, and syndromes of intellectual disability and epilepsy. In Dcx−/Y mice, CA3 hippocampal pyramidal cells are abnormally laminated. The lamination defect was quantified by measuring the extent of the double, dispersed or single pyramidal cell layer in the CA3 region of Dcx−/Y mice. We investigated how this abnormal lamination affected two groups of synapses that normally innervate defined regions of the CA3 pyramidal cell membrane. Numbers of parvalbumin (PV)‐containing interneurons, which contact peri‐somatic sites, were not reduced in Dcx−/Y animals. Pyramidal cells in double, dispersed or single layers received PV‐containing terminals. Excitatory mossy fibres which normally target proximal CA3 pyramidal cell apical dendrites apparently contact CA3 cells of both layers in Dcx−/Y animals but sometimes on basilar rather than apical dendrites. The dendritic form of pyramidal cells in Dcx−/Y animals was altered and pyramidal cells of both layers were more excitable than their counterparts in wild‐type animals. Unitary inhibitory field events occurred at higher frequency in Dcx−/Y animals. These differences may contribute to a susceptibility to epileptiform activity: a modest increase in excitability induced both interictal and ictal‐like discharges more effectively in tissue from Dcx−/Y mice than from wild‐type animals.
We report data on the neuronal form, synaptic connectivity, neuronal excitability and epileptiform population activities generated by the hippocampus of animals with an inactivated doublecortin gene. The protein product of this gene affects neuronal migration during development.
Summary
Purpose: Epilepsy is a significant long‐term consequence of traumatic brain injury (TBI) and is likely to result from multiple mechanisms. One feature that is common to many forms of TBI is ...denervation. We asked whether chronic partial denervation in vivo would lead to a homeostatic increase in the excitability of a denervated cell population.
Methods: To answer this question, we took advantage of the unique anatomy of the hippocampus where the input to the CA1 neurons, the Schaffer collaterals, could be transected in vivo with preservation of their outputs and only minor cell death.
Key Findings: We observed a delayed increase in neuronal excitability, as apparent in extracellular recordings from hippocampal brain slices prepared 14 days (but not 3 days) post lesion. Although population spikes in slices from control and lesioned animals were comparable under resting conditions, application of solutions that were mildly proconvulsive (high K+, low Mg2+, low concentrations of bicuculline) produced increases in the number of population spikes in slices from lesioned rats, but not in slices from unlesioned sham controls. Denervation did not produce changes in several markers of γ‐aminobutyric acid (GABA)ergic synaptic inhibition, including the number of GABAergic neurons, α1 GABAA receptor subunits, the vesicular GABA transporter, or miniature inhibitory postsynaptic currents.
Significance: We conclude that chronic partial denervation does lead to a delayed homeostatic increase in neuronal excitability, and may, therefore, contribute to the long‐term neurologic consequences of TBI.
Patients with Doublecortin (DCX) mutations have severe cortical malformations associated with mental retardation and epilepsy. Dcx knockout (KO) mice show no major isocortical abnormalities, but have ...discrete hippocampal defects. We questioned the functional consequences of these defects and report here that Dcx KO mice are hyperactive and exhibit spontaneous convulsive seizures. Changes in neuropeptide Y and calbindin expression, consistent with seizure occurrence, were detected in a large proportion of KO animals, and convulsants, including kainate and pentylenetetrazole, also induced seizures more readily in KO mice. We show that the dysplastic CA3 region in KO hippocampal slices generates sharp wave-like activities and possesses a lower threshold for epileptiform events. Video-EEG monitoring also demonstrated that spontaneous seizures were initiated in the hippocampus. Similarly, seizures in human patients mutated for DCX can show a primary involvement of the temporal lobe. In conclusion, seizures in Dcx KO mice are likely to be due to abnormal synaptic transmission involving heterotopic cells in the hippocampus and these mice may therefore provide a useful model to further study how lamination defects underlie the genesis of epileptiform activities.
Penetrating head injuries are often accompanied by the delayed development of post‐traumatic epilepsy. Schaffer collateral transection leads to axonal sprouting and hyperexcitability in area CA3 of ...hippocampal slice cultures. We used this model to test the hypothesis that the injury‐induced axonal sprouting results from increased neurotrophin signaling via trkB receptors near the lesion. Using rats and mice, we established that sprouting CA3 pyramidal cell axons are labeled with an antibody to the growth‐associated protein GAP‐43. We observed two‐ to threefold increases in the level of brain‐derived neurotrophic factor and trkB protein in area CA3 by 24–48 h after Schaffer collateral transection, preceding the onset of axonal sprouting. Finally, we demonstrated that injury‐induced axonal sprouting of GAP‐43‐immunoreactive axons is impaired in hippocampal slice cultures from mice expressing low levels of trkB receptors. We conclude that injury‐induced axonal sprouting is initiated by brain‐derived neurotrophic factor–trkB signaling and suggest that this process may be critical for the genesis of post‐traumatic epilepsy.
Increasing industrial and military use of uranium has led to environmental pollution, which may result in uranium reaching the brain and causing cerebral dysfunction. A recent literature review has ...discussed data published over the last 10 years on uranium and its effects on brain function (Dinocourt C, Legrand M, Dublineau I, et al., Toxicology 337:58-71, 2015). New models of uranium exposure during neonatal brain development and the emergence of new technologies (omics and epigenetics) are of value in identifying new specific targets of uranium. Here we review the latest studies of neurogenesis, epigenetics, and metabolic dysfunctions and the identification of new biomarkers used to establish potential pathophysiological states of neurodevelopmental and neurodegenerative diseases.
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