Triclosan Impairs Hippocampal Synaptic Plasticity and Spatial Memory in Male Rats.

Triclosan, a widely used industrial and household agent, is present as an antiseptic ingredient in numerous products of everyday use, such as toothpaste, cosmetics, kitchenware, and toys. Previous studies have shown that human brain and animal tissues contain triclosan, which has been found also as a contaminant of water and soil. Triclosan disrupts heart and skeletal muscle Ca2+ signaling, damages liver function, alters gut microbiota, causes colonic inflammation, and promotes apoptosis in cultured neocortical neurons and neural stem cells. Information, however, on the possible effects of triclosan on the function of the hippocampus, a key brain region for spatial learning and memory, is lacking. Here, we report that triclosan addition at low concentrations to hippocampal slices from male rats inhibited long-term potentiation but did not affect basal synaptic transmission or paired-pulse facilitation and modified the content or phosphorylation levels of synaptic plasticity-related proteins. Additionally, incubation of primary hippocampal cultures with triclosan prevented both the dendritic spine remodeling induced by brain-derived neurotrophic factor and the emergence of spontaneous oscillatory Ca2+ signals. Furthermore, intra-hippocampal injection of triclosan significantly disrupted rat navigation in the Oasis maze spatial memory task, an indication that triclosan impairs hippocampus-dependent spatial memory performance. Based on these combined results, we conclude that triclosan exerts highly damaging effects on hippocampal neuronal function in vitro and impairs spatial memory processes in vivo.

Iron deficiency on neuronal function.

Because of the intrinsic ability of iron to catalyze the formation of reactive oxygen species, it has been associated with oxidative stress and neurodegenerative diseases. However, iron deficiency (ID) also negatively impacts various functions of the brain, suggesting that iron plays an important physiological role in neuronal processes such as myelination, synaptogenesis, behavior and synaptic plasticity (SP). ID not only produces changes in the hippocampus, striatum, amygdale or prefrontal cortex, it also affects the interaction among these systems. In both humans and rodents, the perturbations of these structures are associated to cognitive deficits. These cognitive alterations have been well correlated with changes in neural plasticity, the possible cellular substrate of memory and learning. Given that SP is strongly affected by early ID and the lasting-neurological consequences remain even after ID has been corrected, it is important to prevent ID as well as to seek effective therapeutic interventions that reduce or reverse the long-term effects of the ID in the nervous system. This review will give an overview of the literature on the effects of iron deficit in neuronal functions such as behavior, neurotransmission and SP. We also discuss our recent data about the possible oxidative effect of iron on the mechanisms involved in neural plasticity.

Iron mediates N-methyl-D-aspartate receptor-dependent stimulation of calcium-induced pathways and hippocampal synaptic plasticity.

Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-D-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine-reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP.

Effects of ATP, Mg2+, and redox agents on the Ca2+ dependence of RyR channels from rat brain cortex.

Despite their relevance for neuronal Ca(2+)-induced Ca(2+) release (CICR), activation by Ca(2+) of ryanodine receptor (RyR) channels of brain endoplasmic reticulum at the [ATP], [Mg(2+)], and redox conditions present in neurons has not been reported. Here, we studied the effects of varying cis-(cytoplasmic) free ATP concentration ([ATP]), [Mg(2+)], and RyR redox state on the Ca(2+) dependence of endoplasmic reticulum RyR channels from rat brain cortex. At pCa 4.9 and 0.5 mM adenylylimidodiphosphate (AMP-PNP), increasing free [Mg(2+)] up to 1 mM inhibited vesicular [(3)H]ryanodine binding; incubation with thimerosal or dithiothreitol decreased or enhanced Mg(2+) inhibition, respectively. Single RyR channels incorporated into lipid bilayers displayed three different Ca(2+) dependencies, defined by low, moderate, or high maximal fractional open time (P(o)), that depend on RyR redox state, as we have previously reported. In all cases, cis-ATP addition (3 mM) decreased threshold [Ca(2+)] for activation, increased maximal P(o), and shifted channel inhibition to higher [Ca(2+)]. Conversely, at pCa 4.5 and 3 mM ATP, increasing cis-[Mg(2+)] up to 1 mM inhibited low activity channels more than moderate activity channels but barely modified high activity channels. Addition of 0.5 mM free [ATP] plus 0.8 mM free [Mg(2+)] induced a right shift in Ca(2+) dependence for all channels so that [Ca(2+)] <30 microM activated only high activity channels. These results strongly suggest that channel redox state determines RyR activation by Ca(2+) at physiological [ATP] and [Mg(2+)]. If RyR behave similarly in living neurons, cellular redox state should affect RyR-mediated CICR.