The effect of long-term rapamycin treatment on hippocampal synaptic function in a mouse model of Alzheimer's disease
Alzheimer's disease is a neurodegenerative disease leading to progressive loss of memory and is characterized by accumulation and aggregation of Amyloid beta. The immunosuppressant drug rapamycin binds to its receptor called the mammalian target of rapamycin (mTOR). mTOR, along with many other roles, depresses autophagy of proteins. Thus, binding of rapamycin to mTOR inactivates it and likely increases autophagy to rid the neurons of increasing levels of Amyloid beta; in the system.
Results suggested that rapamycin had no significant effect in the CA1 of the hippocampus on neuronal excitability, basal synaptic transmission, synaptic efficacy, and short-term plasticity, but had a peculiar effect on long-term synaptic plasticity (LTP).
A model of LTP involving the alteration in the excitation to inhibition ratio in the CA1 region of the hippocampal neuronal circuitry was prepared to understand the effect of rapamycin. Using Monte Carlo simulations it was found that rapamycin likely restores the excitation to inhibition ratio by removing the inhibition of GABAergic neurons that resulted due to LTP induction. As the excitation to inhibition ratio is crucial for the proper regulation of the entire neuronal circuitry, the effect of rapamycin on this ratio could be of critical importance.