| First Author | Li W | Year | 2017 |
| Journal | Dis Model Mech | Volume | 10 |
| Issue | 7 | Pages | 837-845 |
| PubMed ID | 28679669 | Mgi Jnum | J:244187 |
| Mgi Id | MGI:5912966 | Doi | 10.1242/dmm.029959 |
| Citation | Li W, et al. (2017) A small-molecule TrkB ligand restores hippocampal synaptic plasticity and object location memory in Rett syndrome mice. Dis Model Mech 10(7):837-845 |
| abstractText | Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein-2 (MECP2), a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are reduced in RTT autopsy brains and in multiple brain areas of Mecp2-deficient mice. Furthermore, experimental interventions that increase BDNF levels improve RTT-like phenotypes in Mecp2 mutant mice. Here, we characterized the actions of a small-molecule ligand of the BDNF receptor TrkB in hippocampal function in Mecp2 mutant mice. Systemic treatment of female Mecp2 heterozygous (HET) mice with LM22A-4 for 4 weeks improved hippocampal-dependent object location memory and restored hippocampal long-term potentiation (LTP). Mechanistically, LM22A-4 acts to dampen hyperactive hippocampal network activity, reduce the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), and reduce the frequency of spontaneous tetrodotoxin-resistant Ca2+ signals in Mecp2 mutant hippocampal neurons, making them comparable to those features observed in wild-type neurons. Together, these observations indicate that LM22A-4 is a promising therapeutic candidate for the treatment of hippocampal dysfunction in RTT. |
