Microglia-mediated calcium-permeable AMPAR accumulation in the nucleus accumbens drives hyperlocomotion during cocaine withdrawal.

During withdrawal from cocaine, calcium permeable-AMPA receptors (CP-AMPAR) progressively accumulate in nucleus accumbens (NAc) synapses, a phenomenon linked to behavioral sensitization and drug-seeking. Recently, it has been suggested that neuroimmune alterations might promote aberrant changes in synaptic plasticity, thus contributing to substance abuse-related behaviors. Here, we investigated the role of microglia in NAc neuroadaptations after withdrawal from cocaine-induced conditioned place preference (CPP). We depleted microglia using PLX5622-supplemented diet during cocaine withdrawal, and after the place preference test, we measured dendritic spine density and the presence of CP-AMPAR in the NAc shell. Microglia depletion prevented cocaine-induced changes in dendritic spines and CP-AMPAR accumulation. Furthermore, microglia depletion prevented conditioned hyperlocomotion without affecting drug-context associative memory. Microglia displayed fewer number of branches, resulting in a reduced arborization area and microglia control domain at late withdrawal. Our results suggest that microglia are necessary for the synaptic adaptations in NAc synapses during cocaine withdrawal and therefore represent a promising therapeutic target for relapse prevention.

Epigallocatechin gallate (EGCG) inhibits adhesion and migration of neural progenitor cells in vitro.

Food supplements based on herbal products are widely used during pregnancy as part of a self-care approach. The idea that such supplements are safe and healthy is deeply seated in the general population, although they do not underlie the same strict safety regulations than medical drugs. We aimed to characterize the neurodevelopmental effects of the green tea catechin epigallocatechin gallate (EGCG), which is now commercialized as high-dose food supplement. We used the "Neurosphere Assay" to study the effects and unravel underlying molecular mechanisms of EGCG treatment on human and rat neural progenitor cells (NPCs) development in vitro. EGCG alters human and rat NPC development in vitro. It disturbs migration distance, migration pattern, and nuclear density of NPCs growing as neurospheres. These functional impairments are initiated by EGCG binding to the extracellular matrix glycoprotein laminin, preventing its binding to ß1-integrin subunits, thereby prohibiting cell adhesion and resulting in altered glia alignment and decreased number of migrating young neurons. Our data raise a concern on the intake of high-dose EGCG food supplements during pregnancy and highlight the need of an in vivo characterization of the effects of high-dose EGCG exposure during neurodevelopment.

Two cholinesterase inhibitors trigger dissimilar effects on behavior and body weight in C57BL/6 mice: The case of chlorpyrifos and rivastigmine.

Cholinesterases (ChE) are common targets of organophosphate (OP) pesticides and play a critical role in the pathology of some dementias. While chlorpyrifos (CPF) remains one of the most commonly used OPs in the world, numerous investigations have reported its neurotoxic potential and highlighted behavioral disturbances upon its administration. Rivastigmine currently serves to treat Alzheimer's disease, but it may induce cholinergic overstimulation in non-demented individuals. The present investigation aimed to compare the acute and delayed effects caused by both ChE inhibitors in adult C57BL/6 male mice. The animals were daily fed either a standard, a CPF- (5mg/kg body weight) or a rivastigmine-supplemented diet (1 or 2mg/kg body weight) for 8 weeks. After the treatment, we established an 8-week washout period to assess recovery. ChE enzyme activity, biomarkers, physical effects, and behavioral alterations were evaluated at different time points during the exposure and after the washout period. Both rivastigmine doses induced a time-dependent weight increase. CPF and rivastigmine inhibited brain acetylcholinesterase following an isoform-specific pattern. As for behavioral assessment, CPF negatively modulated learning strategies and impaired memory in a Barnes maze task at the end of the exposure. On the other hand, the low dose of rivastigmine improved memory recall at the end of the washout period in a Morris water maze. Indeed, our results endorse the positive effects of low doses of rivastigmine following a drug-free period in young mice. Therefore, doses and periodicity of treatment to improve cognition in elderly people upon rivastigmine administration should be revised.

Chronic exposure to chlorpyrifos triggered body weight increase and memory impairment depending on human apoE polymorphisms in a targeted replacement mouse model.

Despite restrictions on their use, humans are still constantly exposed to organophosphates (OPs). A huge number of studies have ratified the neurotoxic effects of chlorpyrifos (CPF) and suggested its association with neurodegenerative diseases, but data are still scarce. Human apolipoprotein E (apoE) plays an important role in lipid transport and distribution. In humans, the apoE4 isoform has been linked to an increased risk of Alzheimer's disease (AD). ApoE3 is the most prevalent isoform worldwide, and has been often established as the healthful one. The current study, performed in targeted replacement (TR) adult male mice, aimed to inquire whether genetic variations of the human apoE respond differently to a chronic dietary challenge with CPF. At four/five months of age, mice carrying apoE2, apoE3 or apoE4 were pair-fed a diet supplemented with CPF at 0 or 2mg/kg body weight/day for 13weeks. Cholinergic signs were monitored daily and body weight changes weekly. In the last week of treatment, learning and memory were assessed in a Barnes maze task. Dietary CPF challenge increased body weight only in apoE3 mice. Differences in the acquisition and retention of the Barnes maze were attributed to apoE genetic differences. Our results showed that apoE4 mice performed worse than apoE2 and apoE3 carriers in the acquisition period of the spatial task, and that apoE2 mice had poorer retention than the other two genotypes. On the other hand, CPF increased the search velocity of apoE2 subjects during the acquisition period. Retention was impaired only in CPF-exposed apoE3 mice. These results underline that gene×environment interactions need to be taken into account in epidemiological studies. Given that apoE3, the most common polymorphism in humans, has proved to be the most sensitive to CPF, the potential implications for human health merit serious thought.