PMID- 28679669
OWN - NLM
STAT- MEDLINE
DCOM- 20180330
LR  - 20181113
IS  - 1754-8411 (Electronic)
IS  - 1754-8403 (Print)
IS  - 1754-8403 (Linking)
VI  - 10
IP  - 7
DP  - 2017 Jul 1
TI  - A small-molecule TrkB ligand restores hippocampal synaptic plasticity and object 
      location memory in Rett syndrome mice.
PG  - 837-845
LID - 10.1242/dmm.029959 [doi]
AB  - 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 Ca(2+) 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.
CI  - (c) 2017. Published by The Company of Biologists Ltd.
FAU - Li, Wei
AU  - Li W
AD  - Department of Neurobiology, Civitan International Research Center, University of 
      Alabama at Birmingham, Birmingham, AL 35294, USA.
FAU - Bellot-Saez, Alba
AU  - Bellot-Saez A
AD  - Department of Neurobiology, Civitan International Research Center, University of 
      Alabama at Birmingham, Birmingham, AL 35294, USA.
FAU - Phillips, Mary L
AU  - Phillips ML
AD  - Department of Neurobiology, Civitan International Research Center, University of 
      Alabama at Birmingham, Birmingham, AL 35294, USA.
FAU - Yang, Tao
AU  - Yang T
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
FAU - Longo, Frank M
AU  - Longo FM
AD  - Department of Neurology and Neurological Sciences, Stanford University School of 
      Medicine, Stanford, CA 94305, USA.
FAU - Pozzo-Miller, Lucas
AU  - Pozzo-Miller L
AUID- ORCID: 0000-0001-6085-5527
AD  - Department of Neurobiology, Civitan International Research Center, University of 
      Alabama at Birmingham, Birmingham, AL 35294, USA lucaspm@uab.edu.
LA  - eng
GR  - R01 NS065027/NS/NINDS NIH HHS/United States
GR  - R21 HD074418/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Dis Model Mech
JT  - Disease models & mechanisms
JID - 101483332
RN  - 0 (Benzamides)
RN  - 0 (Ligands)
RN  - 0 (Methyl-CpG-Binding Protein 2)
RN  - 0 (N,N',N'-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Benzamides/*pharmacology/*therapeutic use
MH  - Calcium/metabolism
MH  - Excitatory Postsynaptic Potentials/drug effects
MH  - Female
MH  - Heterozygote
MH  - Hippocampus/drug effects/*physiopathology
MH  - Ligands
MH  - Long-Term Potentiation/drug effects
MH  - Male
MH  - Memory/*drug effects
MH  - Methyl-CpG-Binding Protein 2/deficiency/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Motor Activity/drug effects
MH  - Nerve Net/drug effects/physiopathology
MH  - Neuronal Plasticity/*drug effects
MH  - Phenotype
MH  - Receptor, trkB/*metabolism
MH  - Rett Syndrome/*drug therapy/*physiopathology
PMC - PMC5536912
OTO - NOTNLM
OT  - BDNF
OT  - CA1 pyramidal neuron
OT  - Ca2+ imaging
OT  - LM22A-4
OT  - LTP
OT  - MeCP2
OT  - Object location memory
OT  - Voltage-sensitive dye imaging
COIS- Competing interestsF.L. is a founder of PharmatrophiX, a company focused on the 
      development of neurotrophin receptor ligands.
EDAT- 2017/07/07 06:00
MHDA- 2018/03/31 06:00
PMCR- 2017/07/01
CRDT- 2017/07/07 06:00
PHST- 2017/03/13 00:00 [received]
PHST- 2017/05/08 00:00 [accepted]
PHST- 2017/07/07 06:00 [entrez]
PHST- 2017/07/07 06:00 [pubmed]
PHST- 2018/03/31 06:00 [medline]
PHST- 2017/07/01 00:00 [pmc-release]
AID - 10/7/837 [pii]
AID - DMM029959 [pii]
AID - 10.1242/dmm.029959 [doi]
PST - ppublish
SO  - Dis Model Mech. 2017 Jul 1;10(7):837-845. doi: 10.1242/dmm.029959.