Authors: Rachel Coleby, Future Science Group
A research team led by Lucas Pozzo-Miller (University of Alabama at Birmingham; Birmingham, AL, USA) has been investigating the role of brain derived neurotrophic factor (BDNF) in synapses and more recently how this can translate to Rett Syndrome (RTT) therapy.
Pozzo-Miller stated: “In fact, we became interested in RTT due to others groups’ observations of MeCP2 regulation of BDNF expression and genetic overexpression of BDNF improving behavioral deficits in Mecp2 mutant mice.”
Whilst Pozzo-Miller’s group were working on a method to increase BDNF levels, another group based at Stanford University (Stanford, CA, USA) had just developed a small molecule mimetic of BDNF which is also a partial agonist of the TrkB receptor. They termed the molecule LM22A-4 and their research was focused on the neural bases of breathing. Seeing that a cross-over may be possible with their research, Pozzo-Miller’s team began testing the molecule for its ability to enhance synaptic plasticity in the hippocampus, the region responsible for spatial learning and memory.
The results from these studies demonstrated that LM22A-4 was able to improve the hippocampal function in Mecp2 mutant murine models, in particular improving hippocampal-dependant object location memory and restored hippocampal long-term potentiation. The team identified that LM22A-4 initiated these positive effects by dampening hyperactive hippocampal network activity, reducing the frequency and amplitude of miniature excitatory postsynaptic currents and signals, allowing synaptic plasticity to take place.
The results from this study add to the body of literature that supports the hypothesis that LM22A-4 is a promising therapeutic candidate and could provide RTT patients some relief from their symptoms. Pozzo-Miller concluded: “There has been a growing realization that neurodevelopmental disorders need not be considered as closed cases simply because the mutations affect early brain development. Our studies in Rett model mice add to similar studies in mouse models of Down syndrome, neurofibromatosis, tuberous sclerosis and fragile X, which provide rational bases for their treatment in adulthood, providing hope for millions of affected individuals and their families.”
Sources: Li W, Bellot-Saez A, Phillips ML, Yang T, Longo FM and Pozzo-Miller L. A small-molecule TrkB ligand restores hippocampal synaptic plasticity and object location memory in Rett syndrome mice. Dis. Model. Mech. doi: 10.1242/dmm.029959 (Epub ahead of print) (2017); www.sciencedaily.com/releases/2017/07/170705095330.htm