Mauch et al., in a well-designed, interesting study, demonstrate the importance of cholesterol to the formation of electrically functional synapses in cultured retinal ganglion cells. They demonstrate that retinal ganglion cells attain their normal morphology when cultured under serum-free defined conditons in the absence of glial cells. Their synaptic number and activity, however, is low under these conditions. The addition of glial-conditioned media increases synaptic activity and number in these cells. It is shown that fractions of this media containing ApoE-containing lipoproteins account for the effects of the glial-conditioned media in increasing synaptic activity and number. These effects can be mimicked by adding exogenous cholesterol (without ApoE) and inhibited by inhibiting cholesterol synthesis by glia.

The findings demonstrate that adequate levels of cholesterol are required by developing retinal ganglion neurons in culture for attaining normal numbers of functioning synapses.

The findings imply that normal levels of cholesterol in the brain are...  Read more

Mauch et al., in a well-designed, interesting study, demonstrate the importance of cholesterol to the formation of electrically functional synapses in cultured retinal ganglion cells. They demonstrate that retinal ganglion cells attain their normal morphology when cultured under serum-free defined conditons in the absence of glial cells. Their synaptic number and activity, however, is low under these conditions. The addition of glial-conditioned media increases synaptic activity and number in these cells. It is shown that fractions of this media containing ApoE-containing lipoproteins account for the effects of the glial-conditioned media in increasing synaptic activity and number. These effects can be mimicked by adding exogenous cholesterol (without ApoE) and inhibited by inhibiting cholesterol synthesis by glia.

The findings demonstrate that adequate levels of cholesterol are required by developing retinal ganglion neurons in culture for attaining normal numbers of functioning synapses.

The findings imply that normal levels of cholesterol in the brain are critically important during development for normal synapse formation and function. How these findings relate to the importance and role of specific molecules in the brain (in vivo) in this process or to disease conditions is not yet clear. A future study that might be useful would be to test whether the same effects observed in the Mauch et al. study can be seen in mouse retinal ganglion cells cultured on glia derived from apoE -/- vs. wild-type mice.

Whether levels of cholesterol or its delivery to neurons ever becomes so limiting in the brain (as in the culture conditions studied) to result in cholesterol depletion enough to cause decreased synaptic number or efficacy is unknown. ApoE is the most abundant apolipoprotein in brain and it can deliver cholesterol to neurons and glia. Most but not all evidence suggests that synapse formation and number is normal in the CNS of ApoE -/- mice after birth and into development. There may be other molecules and redundant pathways that allow neurons in the CNS to acquire enough cholesterol in the absence of ApoE in vivo to attain normal synaptic number and function. No abnormality in intellect or brain development has been reported in human individuals who lack ApoE. It is certainly conceivable that cholesterol availability becomes abnormal under certain conditions in the aging brain and that ApoE, its isoforms, or other molecules important to cholesterol synthesis and delivery could specifically influence synaptic function. Further studies will be needed to sort out these issues.

View all comments by David Holtzman

The compelling data by Mauch et al. affirms the critical nature of cholesterol in the CNS, particularly the developing CNS. As with most very good research, the experiments lead to important answers and provide the foundation for more questions.

These authors clearly demonstrate that cholesterol/apolipoprotein E are essential for synaptogenesis and probably for appropriate production and transportation of organelles (i.e. vesicles) necessary for neurotransmission. Coupled with the understanding that a large portion of a developing growth cone is cholesterol, this suggests that a pathologic condition or centrally acting agent, which disrupts cholesterol metabolism, could be devastating to a human infant, both pre- and postpartum.

If one accepts the concept that there is plasticity to synaptic contact in the mature CNS in that synaptic contacts may be formed, dissolved, and reformed as necessary, then directly altering cholesterol metabolism in the adult brain could also have deleterious consequences.

Some believe that sprouting and an attempt to re-connect lost...  Read more

The compelling data by Mauch et al. affirms the critical nature of cholesterol in the CNS, particularly the developing CNS. As with most very good research, the experiments lead to important answers and provide the foundation for more questions.

These authors clearly demonstrate that cholesterol/apolipoprotein E are essential for synaptogenesis and probably for appropriate production and transportation of organelles (i.e. vesicles) necessary for neurotransmission. Coupled with the understanding that a large portion of a developing growth cone is cholesterol, this suggests that a pathologic condition or centrally acting agent, which disrupts cholesterol metabolism, could be devastating to a human infant, both pre- and postpartum.

If one accepts the concept that there is plasticity to synaptic contact in the mature CNS in that synaptic contacts may be formed, dissolved, and reformed as necessary, then directly altering cholesterol metabolism in the adult brain could also have deleterious consequences.

Some believe that sprouting and an attempt to re-connect lost circuits occurs in neurodegenerative disorders. If that is so, the effect of altering cholesterol metabolism could depend on whether or not re-connection is faithful. It is possible that misconnection of synaptic circuitry (innervating the wrong target) could be worse than the result of the neurodegeneration alone. In this case it may be appropriate to attempt to attenuate such misguided synaptogenesis. These are only possibilities that await further clarification.

View all comments by Larry Sparks