A small-molecule TrkB ligand restores hippocampal synaptic plasticity and object location memory in Rett syndrome mice

Dis Model Mech. 2017 Jul 1;10(7):837-845. doi: 10.1242/dmm.029959.

Abstract

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.

Keywords: BDNF; CA1 pyramidal neuron; Ca2+ imaging; LM22A-4; LTP; MeCP2; Object location memory; Voltage-sensitive dye imaging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use*
  • Calcium / metabolism
  • Excitatory Postsynaptic Potentials / drug effects
  • Female
  • Heterozygote
  • Hippocampus / drug effects
  • Hippocampus / physiopathology*
  • Ligands
  • Long-Term Potentiation / drug effects
  • Male
  • Memory / drug effects*
  • Methyl-CpG-Binding Protein 2 / deficiency
  • Methyl-CpG-Binding Protein 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Nerve Net / drug effects
  • Nerve Net / physiopathology
  • Neuronal Plasticity / drug effects*
  • Phenotype
  • Receptor, trkB / metabolism*
  • Rett Syndrome / drug therapy*
  • Rett Syndrome / physiopathology*

Substances

  • Benzamides
  • Ligands
  • Methyl-CpG-Binding Protein 2
  • N,N',N'-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide
  • Receptor, trkB
  • Calcium