Dendritic spines are specialized protrusions responsible for receiving excitatory synaptic inputs, providing an important function in communication between neurons. The majority of excitatory synapses in the brain exist on dendritic spines. Accordingly, the regulation of dendritic spine density in the hippocampus is thought to play a central role in learning and memory. The development of novel methods to control spine density could, therefore, have important implications for treatment of a host of neurodegenerative and developmental cognitive disorders. Now, researchers at the University of California San Diego have designed a set of molecules that promote microscopic, anatomical changes in neurons associated with the formation and retention of memories. The team state that these drug candidates also prevent deterioration of the same neuronal structures in the presence of amyloid-beta, a protein fragment that accumulates in the brains of people with Alzheimer’s disease. The opensource study is published in the Journal of Biological Chemistry.
Earlier studies from the lab show older versions of these compounds improved memory and learning in normal mice and a mouse model for Alzheimer’s disease, however, they were too toxic to pursue as drug candidates. Therefore, the group worked out a way to keep the part of the molecules that they believe promoted the growth of dendritic spines, and altered the chemical features that impart toxicity. These novel compounds, called benzothiazole amphiphiles, have been shown to be new tools to study relationship between dendritic spines and cognitive behaviour. The current study looked at the effect of this drug candidate on the density of dendritic spines in primary hippocampal neurons, a region of the brain crucial for memory.
The current study utilised treated neurons from a part of the brain critical to forming and retrieving memories with their new compounds they saw an increase in the density of dendritic spines. Results show that time-lapse imaging of dissociated hippocampal neuronal cultures shows that these compounds promote a net increase in spine density through the formation of new spines. Data findings show that an increase in spine density can persist for days in the presence of these compounds, and returns to normal spine density levels within 24 hours when the compounds are removed, demonstrating the capability to reversibly control spinogenic activity.
Results show that the new compounds prevented the loss of these spines that occurs in the presence of amyloid-beta, the substance that forms amyloid plaques in the brains of people with Alzheimer’s disease. Data findings show that the greater the concentration of the drug candidate, the greater the density of spines within the range of doses tested. The lab note that the effect is also reversible and once the compounds were washed away, the spines receded within 24-hours.
The team surmise that the compounds they have developed may offer the possibility to compensate, or ideally preserve, neuronal communication in people suffering from problems with memory. They go on to add that it is known from a wealth of prior research that spine densities on neurons change over time and that increases in the densities correlate with improved memory and learning. For the future, the researchers state that as potential drugs, benzothiazole amphiphiles could be useful for combatting spine loss in neurodegenerative disease, or possibly for general cognitive enhancement.
Tiny thornlike structures along the branches of this neuron are dendritic spines, which form the receiving end of synapses. Treatment with a novel compound induced the cell to sprout 20 to 25 percent more spines than a normal, untreated neuron. Credit: Jessica Cifelli.
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