Several neurodegenerative disorders are associated with impaired cholesterol homeostasis in the nervous system where cholesterol is known to play a role in modulating synaptic activity and stabilizing membrane microdomains. In the present report, we investigated the effects of methyl-β-cyclodextrin-induced cholesterol depletion on synaptic transmission and on the expression of 1) paired-pulse facilitation (PPF); 2) paired-pulse inhibition (PPI) and 3) long-term potentiation (LTP) in the CA1 hippocampal region. Results demonstrated that cyclodextrin strongly reduced synaptic transmission and blocked the expression of LTP, but did not affect PPF and PPI. The role of glutamatergic and GABAergic receptors in these cholesterol depletion-mediated effects was evaluated pharmacologically. Data indicate that, in cholesterol depleted neurons, modulation of synaptic transmission and synaptic plasticity phenomena are sustained by AMPA-, kainate-and NMDA-receptors but not by GABA-receptors. The involvement of AMPA-and kainate-receptors was confirmed by fluorimetric analysis of intracellular calcium concentrations in hippocampal cell cultures. These data suggest that modulation of receptor activity by manipulation of membrane lipids is a possible therapeutic strategy in neurodegenerative disease.

Changes in the performance of genotypes in different environments are defined as genotype × environment (G×E) interactions. In grapevine (Vitis vinifera), complex interactions between different genotypes and climate, soil and farming practices yield unique berry qualities. However, the molecular basis of this phenomenon remains unclear. To dissect the basis of grapevine G×E interactions we characterized berry transcriptome plasticity, the genome methylation landscape and within-genotype allelic diversity in two genotypes cultivated in three different environments over two vintages. We identified, through a novel data-mining pipeline, genes with expression profiles that were: unaffected by genotype or environment, genotype-dependent but unaffected by the environment, environmentally-dependent regardless of genotype, and G×E-related. The G×E-related genes showed different degrees of within-cultivar allelic diversity in the two genotypes and were enriched for stress responses, signal transduction and secondary metabolism categories. Our study unraveled the mutual relationships between genotypic and environmental variables during G×E interaction in a woody perennial species, providing a reference model to explore how cultivated fruit crops respond to diverse environments. Also, the pivotal role of vineyard location in determining the performance of different varieties, by enhancing berry quality traits, was unraveled.

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Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1−/− mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1−/− mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1−/− mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia.

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