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Electrophysiological monitoring of SE in hippocampal neurons. Culture dishes were incubated in control or low Mg 2+ solutions and neurons were patch clamped using the whole-cell current-clamp mode as described in Materials and Methods. Scale bar described in part B is applicable to all traces. (A) Representative recording of a neuron incubated in control solution. (B) Representative trace of a neuron incubated in low Mg 2+ solution for approximately 1 h. (C) Representative recording of a neuron incubated in low Mg 2+ solution for approximately 3 h.
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![Figure 6. Changes in [Ca 2+ ]i in hippocampal neurons during SE....](profile/Laxmikant-Deshpande/publication/342923494/figure/fig3/AS:913205773750273@1594736631934/Changes-in-Ca-2-i-in-hippocampal-neurons-during-SE-Culture-dishes-were-incubated-in_Q320.jpg)
Loss of intracellular calcium homeostasis is an established mechanism associated with neuronal dysfunction and status epilepticus. Sequestration of free cytosolic calcium into endoplasmic reticulum by Mg 2+ /Ca 2+ adenosinetriphosphatase (ATPase) is critical for maintenance of intracellular calcium homeostasis. Exposing hippocampal cultures to low-...
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Context 1
... discharges in hippocampal neurons in culture are commonly monitored using whole-cell current-clamp methodology [27,32,33]. Figure 1 shows typical patch-clamp traces of neurons incubated in control or low Mg 2+ solutions. Control neurons exhibited a mean membrane potential of −61.2 ± 2.5 mV and a mean input resistance of 120.6 ± 7.4 MΩ, whereas the low Mg 2+ neurons demonstrated a mean membrane potential of −59.8 ± 2.1 mV and a mean input resistance of 118.9 ± 8.4 MΩ. ...
Context 2
... discharges in hippocampal neurons in culture are commonly monitored using whole-cell current-clamp methodology [27,32,33]. Figure 1 shows typical patch-clamp traces of neurons incubated in control or low Mg 2+ solutions. Control neurons exhibited a mean membrane potential of −61.2 ± 2.5 mV and a mean input resistance of 120.6 ± 7.4 MΩ, whereas the low Mg 2+ neurons demonstrated a mean membrane potential of −59.8 ± 2.1 mV and a mean input resistance of 118.9 ± 8.4 MΩ. ...
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Citations
... In fact, mutations in proteins that regulate ion homeostasis, such as transmembrane channels and transporters expressed in the neuronal plasma membrane or in organelles, have been associated with epilepsy (Rajakulendran et al. 2012;Veeramah et al. 2013;Deng et al. 2014). The alterations in ion homeostasis that have been associated with epilepsy involve potassium, protons and chloride (Fisher et al. 1976;Staley et al. 1995;Ransom et al. 2000;Raimondo et al. 2013;Deshpande et al. 2020;Thouta et al. 2021). In summary, the function of the transporters of these ions is compromised in some forms of epilepsy, leading to alterations in ion homeostasis during neuronal activity, which are coupled to an imbalance of inhibition in favor of excitation. ...
Epilepsy is a neurological disease characterized by abnormal or synchronous brain activity causing seizures, which may produce convulsions, minor physical signs, or a combination of symptoms. These disorders affect approximately 65 million people worldwide, from all ages and genders. Seizures apart, epileptic patients present a high risk to develop neuropsychological comorbidities such as cognitive deficits, emotional disturbance, and psychiatric disorders, which severely impair quality of life. Currently, the treatment for epilepsy includes the administration of drugs or surgery, but about 30% of the patients treated with antiepileptic drugs develop time-dependent pharmacoresistence. Therefore, further investigation about epilepsy and its causes is needed to find new pharmacological targets and innovative therapeutic strategies. Pharmacoresistance is associated to changes in neuronal plasticity and alterations of GABAA receptor-mediated neurotransmission. The downregulation of GABA inhibitory activity may arise from a positive shift in GABAA receptor reversal potential, due to an alteration in chloride homeostasis. In this paper, we review the contribution of K+-Cl−-cotransporter (KCC2) to the alterations in the Cl– gradient observed in epileptic condition, and how these alterations are coupled to the increase in the excitability.
Organophosphates (OP) are one of the most common neurotoxic xenobiotics. In acute OP poisoning, as a result of suppression of synaptic acetylcholinesterase (AChE) activity, a cholinergic syndrome develops, which can transform into status epilepticus. Within a few days after acute poisoning, the so-called an intermediate syndrome can develop, which is associated with prolonged inhibition of AChE, desensitization of nicotinic receptors, and functional degradation of synapses and muscle fibers. In 10–20 days after a single acute or repeated subacute poisoning, OP-induced delayed polyneuropathy (OPIDN) can develop – a neurodegenerative disease, the signs of which are ataxia, loss of function of the distal sensory and motor axons of peripheral nerves. The occurrence of a neuropsychiatric disorder (NPD) caused by chronic exposure to relatively low-toxicity organophosphorus compounds is usually not associated with acute poisoning; symptoms include cognitive impairment, chronic fatigue, and extrapyramidal symptoms. The list of possible diseases or pathological conditions (syndromes) that develop as a result of acute, subacute or chronic effects of OP on the human body has expanded in recent years due a number of known neurodegenerative diseases (Alzheimer’s, Parkinson’s, multiple sclerosis, etc.). The aging of the body in general and the aging of the brain in particular are considered in the review from the point of view of the consequences of OP poisoning, which can serve as a nonspecific trigger of aging and related neurodegenerative diseases. Gulf syndrome is not a consequence of OP intoxication, but is also of interest and is considered in the context of OP-induced pathology, since its etiology and pathogenesis are associated with the exposure to cholinesterase inhibitors. The review presents data indicating the important role of the vascular endothelium in the development of OP-induced pathology; The first suggestions were made by clinicians in the late 1980s, and the first experimental data were obtained in the early 2000s. The principles of therapy for acute poisoning are outlined, taking into account experimental data from recent years. Some methods for studying OP in experiments in vitro, ex vivo and in vivo with laboratory animals, including the use of carboxylesterase inhibitors, are presented. The most important part of in vivo investigations has been and remains the search for new biomarkers to assess the effectiveness of adjuvant and regenerative therapies.
Biological activities require a delicate balance between excitatory and inhibitory signals in the brain. Disruption of this balance could lead to neurological disorders, such as epilepsydue to a relative enhancement of excitatory signals. In general, cytosolic calcium plays a key role in the transmission of excitatory signals mainly by promoting the release of synaptic vesicles containing neurotransmitters. A series of molecular components responsible for maintaining intracellular calcium homeostasis, including voltage-gated calcium (CaV) channels, the endoplasmic reticulum (ER) calcium sensor stromal interaction molecule (STIM), the PM calcium channel Orai, ER-resident inositol trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs), sarco-endoplasmic reticulum calcium ATPase (SERCA), and transmembrane and coiled-coil domains 1 (TMCO1), have been demonstrated to be involved in calcium dysregulation that underlies epileptic seizures. More importantly, epileptic phenotypes were confirmed in several molecular components by transgenic animal models, including CACNA1A, CACNA1E, CACNA1G, CACNA2D1, ORAI1 and IP3R1. Calcium-binding proteins (CaBPs), such as calmodulin, parvalbumin, calretinin, and calbindin, provide an additional layer of defense by acting as calcium reservoirs to buffer rapid increases in cytosolic calcium concentrations and participate in cellular functions by regulating the activities of ion channels or acting as calcium-modulated sensors, and a series of lines of evidence support their implication with epileptic activities. Overall, stroke represents the most common environmental cause of acquired epilepsy in older adults, and preventing calcium disruption due to reperfusion injury might be an effective way to treat acute symptomatic seizures and decrease the risk for acquired poststroke epilepsy.
Excess molybdenum (Mo) and cadmium (Cd) are harmful to animals, but neurotoxicity caused by Mo and Cd co-exposure in ducks is yet unknown. To assess joint impacts of Mo and Cd on autophagy via calcium homeostasis and unfolded protein response (UPR) in duck brain, 40 healthy 7-day-old ducks (Anas platyrhyncha) were assigned to 4 groups at random and fed diets supplemented with different doses of Mo or/and Cd for 16 weeks, respectively. Brain tissues were excised for experiment. Results exhibited that Mo or/and Cd disturbed calcium homeostasis by decreased ATPase activities and increased calcium (Ca) content, and upregulated calcium homeostasis–related factors Ca²⁺/CAM-dependent kinase IIɑ (CaMKIIɑ), calcineurin (CaN), inositol-1,4,5-trisphosphate receptor (IP3R), and calreticulin (CRT) expression levels. Meanwhile, the upregulation of UPR-related factor expression levels indicated that Mo or/and Cd activated UPR. Moreover, Mo or/and Cd triggered autophagy through promoting the number of autophagosomes and LC3II immunofluorescence intensity and altering autophagy key factor expression levels. Correlation analysis showed that there were obvious connections among Ca²⁺ homeostasis, endoplasmic reticulum (ER) stress, and autophagy induced by Mo or/and Cd. Thence, it can be speculated that autophagy initiated by Mo or/and Cd may be associated with interfering Ca²⁺ homeostasis and triggering UPR.
