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Author Notes:

Correspondence: Giorgio Aicardi giorgio.aicardi@unibo.it; Elisabetta Ciani elisabetta.ciani@unibo.it

These authors have contributed equally to this work: ER, VR, and ST

EC, GA, ST, and VR designed the study.

ER, VR, ST, CF, GM, LG, ML, and GG performed the experiments.

ER, VR, ST, and RR analyzed the data.

KY executed the R13 synthesis.

EC and GA wrote the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Subjects:

Research Funding:

This work was supported by the Telethon Foundation (Grant No. GGP15098 to EC) and by the Italian parent association “CDKL5 insieme verso la cura.”

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • CDKL5
  • synaptic plasticity
  • TrkB
  • PLC gamma 1
  • dendritic pattern
  • GluA2
  • perirhinal cortex
  • rett syndrome
  • LONG-TERM POTENTIATION
  • SYNAPTIC PLASTICITY
  • INFANTILE SPASMS
  • PHOSPHOLIPASE-C
  • MUTATIONS
  • RECEPTOR
  • GENE
  • 7,8-DIHYDROXYFLAVONE
  • MECHANISMS
  • FLAVONOIDS

Functional and Structural Impairments in the Perirhinal Cortex of a Mouse Model of CDKL5 Deficiency Disorder Are Rescued by a TrkB Agonist

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Journal Title:

Frontiers in Cellular Neuroscience

Volume:

Volume 13

Publisher:

, Pages 169-169

Type of Work:

Article | Final Publisher PDF

Abstract:

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe X-linked neurodevelopmental encephalopathy caused by mutations in the CDKL5 gene and characterized by early-onset epilepsy and intellectual and motor impairments. No cure is currently available for CDD patients, as limited knowledge of the pathology has hindered the development of therapeutics. Cdkl5 knockout (KO) mouse models, recently created to investigate the role of CDKL5 in the etiology of CDD, recapitulate various features of the disorder. Previous studies have shown alterations in synaptic plasticity and dendritic pattern in the cerebral cortex and in the hippocampus, but the knowledge of the molecular substrates underlying these alterations is still limited. Here, we have examined for the first time synaptic function and plasticity, dendritic morphology, and signal transduction pathways in the perirhinal cortex (PRC) of this mouse model. Being interconnected with a wide range of cortical and subcortical structures and involved in various cognitive processes, PRC provides a very interesting framework for examining how CDKL5 mutation leads to deficits at the synapse, circuit, and behavioral level. We found that long-term potentiation (LTP) was impaired, and that the TrkB/PLCγ 1 pathway could be mechanistically involved in this alteration. PRC neurons in mutant mice showed a reduction in dendritic length, dendritic branches, PSD-95-positive puncta, GluA2-AMPA receptor levels, and spine density and maturation. These functional and structural deficits were associated with impairment in visual recognition memory. Interestingly, an in vivo treatment with a TrkB agonist (the 7,8-DHF prodrug R13) to trigger the TrkB/PLCγ 1 pathway rescued defective LTP, dendritic pattern, PSD-95 and GluA2-AMPA receptor levels, and restored visual recognition memory in Cdkl5 KO mice. Present findings demonstrate a critical role of TrkB signaling in the synaptic development alterations due to CDKL5 mutation, and suggest the possibility of TrkB-targeted pharmacological interventions.

Copyright information:

© Springer International Publishing AG, part of Springer Nature 2018.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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