Lipid Microdomains in Synapse Formation

Abstract

Membrane lipid rafts (i.e., cholesterol/sphingolipids domains) exhibit functional roles in both healthy and pathological states of the nervous system. However, due to their highly dynamic nature, it remains a challenge to characterize the fundamental aspects of lipid rafts that are important for specific neuronal processes. An experimental approach is presented here that allows for the interfacing of living neurons with an experimentally accessible model membrane where lipid order in cellular rafts can be reproducibly mimicked. It is demonstrated that coexisting lipid microdomains in model membranes can regulate axonal guidance and establish stable presynaptic contacts when interfaced with neurons in vitro. Experimental evidence is provided where specific functional groups and lateral organizations are favored by neurons in establishing synaptic connections. The model membrane platform presented in this work provides an accessible and direct means to investigate how lipid rafts regulate synapse formation. This experimental platform can similarly be extended to explore a variety of other cellular events where lipid lateral organization is believed to be important.

Lipid Rafts: The Maestros of Normal Brain Development

“…Lipid rafts are important for axonal growth and guidance, most likely due to the accumulation of signalling molecules in them [ 114 ]. Some of these are the glycoprotein M6a and ephrinB receptors, which influence the neuronal cytoskeleton [ 115 , 116 ], particularly the actin network [ 11 ], and others are cell adhesion molecules and receptors for the guidance of signalling proteins (e.g., netrin-1) [ 12 , 117 ]. When an axon reaches the postsynaptic target membrane, lipid rafts provide a suitable microenvironment for the formation of a new synapse.…”

“…The brain, with its complex network of neurons and glial cells, relies on the precise coordination of signalling processes for its development, and lipid rafts play a central role in this sophisticated orchestration [ 10 ]. The involvement of lipid rafts in brain development involves several fundamental processes, including neurogenesis, neuronal migration, differentiation and synaptogenesis [ 11 , 12 ]. By compartmentalising cell membranes, lipid rafts create localised environments that facilitate efficient signal transduction, which is crucial for the spatial and temporal regulation of developmental signals.…”

“…Thanks to this unique property, lipid rafts can serve as platforms for bundling signalling molecules, enhancing the specificity and speed of signal propagation essential for coordinated nervous system development [ 13 ]. In addition, lipid rafts are involved in modulating the function of neurotransmitter receptors and the organisation of synaptic components that are critical for synaptic plasticity and the assembly of functional neuronal circuits [ 11 ]. The dynamic nature of lipid rafts combined with their ability to interact with cytoskeletal elements also contributes to the morphological changes that neurons undergo during their development, such as axon formation, dendritic branching, and spine maturation.…”

Artificial Lipid Membranes: Past, Present, and Future

“…Gopalakrishnan et al [ 141 ] demonstrated presynaptic vesicle accumulation on bilayer lipid membranes supported on silica beads (spherically supported membranes). It was later shown in vitro that the existence of lipid microdomains regulates axonal guidance to yield stable presynaptic contacts when interfaced with neurons [ 142 ]; further, it seems that specific functional groups and lateral organizations of the membrane might facilitate synaptic connections. These membrane platforms can interact with living cells and provide a means to investigate the role of membrane heterogeneity in a variety of cellular events.…”