Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus

Abstract

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.

Differential Incorporation of Cholesterol by Sindbis Virus Grown in Mammalian or Insect Cells

“…While derived from a common source, these cells respond very differently to Sindbis virus infection (4,21,22,35), and we anticipated that they might respond differently to delipidated serum. These MEM-E-adapted cells were depleted of cholesterol by the addition of methyl-␤-cyclodextrin (M␤CD) (C-3555; Sigma, ST. Louis, MO) (7,8,13). M␤CD-treated mosquito cells were propagated in MEM-E as described above, with the addition of M␤CD to the measured serum cholesterol at a molar ratio of 8:1 (for FBS lot no.…”

Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

“…The evidence supporting the effects of SIM treatment on NMDA receptor binding density in the brain reveals a possible NMDA antagonist-like effect, which provides an exciting and potential paradigm for decreasing anxiety (Yan et al, 2011;Wang et al, 2009). Cholesterol depletion is reported to lead to an inhibition of Ca 2+ entry induced by NMDA, AMPA, or kainate, inferring that MLRs contribute to the regulation of ionotropic glutamate receptor function (Frank et al, 2008). Therefore, treatment with SIM might affect the functionality of proteins associated with MLRs, such as NMDA receptors.…”

“…Thus, chronic statin therapy may be required before significant effects on CNS cholesterol levels are observed, with reductions in CNS cholesterol possible either directly through direct HMG-CoA reductase inhibition or indirectly via a "sink effect" (Cibičková, 2011). In addition, cholesterol depletion is reported to lead to the inhibition of Ca 2+ entry induced by NMDA, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA), or kainate, inferring that MLRs contribute to the regulation of ionotropic glutamate receptor function (Frank et al, 2008).…”

“…Its channel commonly has a high relative permeability to Ca 2+ , and it is blocked in a voltagedependent manner by magnesium ions such that at resting potential the response is substantially inhibited. Cholesterol depletion is reported to lead to an inhibition of Ca 2+ entry induced by NMDA, AMPA, or kainate, inferring that MLRs contribute to the regulation of ionotropic glutamate receptor function (Egawa et al, 2016;Frank et al, 2008). Numerous post-synaptic density proteins such as NMDA (NR1, NR2A and NR2B), AMPA (GluR1 and GluR2), and metabotropic glutamate receptors (mGluRs) are associated with synaptic MLRs, providing a trans-synaptic link between postsynaptic density proteins and pre-synaptic active zones (Egawa et al, 2016;Kumari, Castillo, Francesconi, 2013).…”

Molecular and structural bases for postsynaptic signal processing: interaction between postsynaptic density and postsynaptic membrane rafts

“…Cholesterol and sphingomyelin, two essential components of membrane rafts, are abundant in the brain and synapses, and affect synaptic development, maintenance, and plasticity. 48,[59][60][61][62][63][64] Presynaptic roles of membrane rafts are evident by the presence of proteins deeply linked to neurotransmitter-release mechanisms (soluble N-ethylmaleimide-sensitive factor attachment protein-receptor (SNARE) proteins, neuronal Ca 2+ sensor 1 (NCS-1), and voltage-dependent Ca 2+ channel Ca v 2.1) in the DRM, and by the impairment of synaptic release associated with decreased cholesterol level. 46 Ganglioside, a main constituent of membrane rafts, is also enriched in the brain 65 and plays a major role in cell-cell recognition and cell signaling.…”