Cholesterol-mediated Neurite Outgrowth Is Differently Regulated between Cortical and Hippocampal Neurons

Abstract

The acquisition of neuronal type-specific morphogenesis is a central feature of neuronal differentiation and has important consequences for region-specific nervous system functions. Here, we report that the cell type-specific cholesterol profile determines the differential modulation of axon and dendrite outgrowths in hippocampal and cerebral cortical neurons in culture. The extent of axon and dendrite outgrowths is greater and the polarity formation occurs earlier in cortical neurons than in hippocampal neurons. The cholesterol concentrations in total homogenate and the lipid rafts from hippocampal neurons are significantly higher than those from cortical neurons. Cholesterol depletion by ␤-cyclodextrin markedly enhanced the neurite outgrowth and accelerated the establishment of neuronal polarity in hippocampal neurons, which were similarly observed in nontreated cortical neurons, whereas cholesterol loading had no effects. In contrast, both depletion and loading of cholesterol decreased the neurite outgrowths in cortical neurons. The stimulation of neurite outgrowth and polarity formation induced by cholesterol depletion was accompanied by an enhanced localization of Fyn, a Src kinase, in the lipid rafts of hippocampal neurons. A concomitant treatment with ␤-cyclodextrin and a Src family kinase inhibitor, PP2, specifically blocked axon outgrowth but not dendrite outgrowth (both of which were enhanced by ␤-cyclodextrin) in hippocampal neurons, suggesting that axon outgrowth modulated by cholesterol is induced in a Fyn-dependent manner. These results suggest that cellular cholesterol modulates axon and dendrite outgrowths and neuronal polarization under culture conditions and also that the difference in cholesterol profile between hippocampal and cortical neurons underlies the difference in neurite outgrowth between these two types of neurons.Neurons contain two types of processes, axons and dendrites, which are structurally and functionally distinct and play different roles in the maintenance of brain functions. There are studies showing the significant role of lipids in the formation of neuronal polarity; it has been shown that phospholipids regulate neurite outgrowth in cultured neurons (1) and that the correct distribution of axonal membrane proteins requires the formation of sphingomyelin/cholesterol-rich microdomains, lipid rafts, and the maturation of the axonal plasma membrane requires the up-regulation of sphingomyelin synthesis (2, 3). Cholesterol also plays a prominent role in raft-mediated trafficking and sorting, because cholesterol depletion by methyl-␤-cyclodextrin impedes trafficking from the trans-Golgi network to the apical membrane (4). It has been shown that cholesterol modulates dendrite outgrowth (5), that its deficiency enhances phosphorylation of tau and axonal depolymerization (6), and that axonal regeneration is dependent on local cholesterol reutilization in vivo (7). In addition, cholesterol supplied as glial lipoproteins stimulates the axon outgrowth of central nervous system neurons...

Ethanol Induces Long-Term Facilitation of NR2B-NMDA Receptor Activity in the Dorsal Striatum: Implications for Alcohol Drinking Behavior

“…Signaling differences in brain regions have been previously reported. For instance, differences in the cholesterol levels in the cortex and hippocampus are suggested to underlie greater outgrowth in cortical neurons than in hippocampal neurons (Ko et al, 2005), and we previously reported that the compartmentalization of Fyn underlies, at least in part, the differences in the actions of ethanol in the hippocampus versus the cortex (Yaka et al, 2003b). Some differences are also found between the dorsal and the ventral striatum.…”

Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells

“…Cholesterol, apart from being an essential component of cellular membranes, is a key regulator of cellular processes in the central nervous system (CNS), playing a role in promoting neurite outgrowth [1][2][3][4][5], in synaptogenesis and synaptic integrity, and in neurotransmitter release [6][7][8][9]. In addition to the brain-specific activities, cholesterol synthesis generates intermediate products, such as isoprenoids and ubiquinone [10].…”

Lipid rafts, cholesterol, and the brain

“…This difference is also present in the detergent resistant membranes, suggesting that hippocampal neurons are also enriched in membrane rafts. Furthermore, the data suggest that cholesterol is a potent regulator of in vitro neuronal morphology: increased cholesterol levels lead to less complex dendritic arborization (Ko et al 2005). Support for this view also comes from an independent study by Pooler et al, in which they report that a Hmgcr inhibitor, pravastatin, enhanced neurite outgrowth, neurite length, and neurite branching in cultured hippocampal neurons (Pooler et al 2006).…”

“…Considering the complexity of adult nervous system, it is not surprising that different brain regions show marked differences in cholesterol content (Zhang et al 1996). In particular, hippocampal and cortical neurons show different intrinsic concentrations of cholesterol (Ko et al 2005). This difference is also present in the detergent resistant membranes, suggesting that hippocampal neurons are also enriched in membrane rafts.…”