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Xu X, Kozikowski AP, Pozzo-Miller L. A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome. Front Cell Neurosci. 2014;8:68doi: 10.3389/fncel.2014.00068.
Xu, X., Kozikowski, A. P., & Pozzo-Miller, L. (2014). A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome. Frontiers in cellular neuroscience, 868. https://doi.org/10.3389/fncel.2014.00068
Xu, Xin, et al. "A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome." Frontiers in cellular neuroscience vol. 8 (2014): 68. doi: https://doi.org/10.3389/fncel.2014.00068
Xu X, Kozikowski AP, Pozzo-Miller L. A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome. Front Cell Neurosci. 2014 Mar 07;8:68. doi: 10.3389/fncel.2014.00068. eCollection 2014. PMID: 24639629; PMCID: PMC3945638.
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Front Cell Neurosci. 2014 Mar 07;8:68. doi: 10.3389/fncel.2014.00068. eCollection 2014.

A selective histone deacetylase-6 inhibitor improves BDNF trafficking in hippocampal neurons from Mecp2 knockout mice: implications for Rett syndrome.

Frontiers in cellular neuroscience

Xin Xu, Alan P Kozikowski, Lucas Pozzo-Miller

Affiliations

  1. Department of Neurobiology, Civitan International Research Center, The University of Alabama at Birmingham Birmingham, AL, USA.
  2. Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago Chicago, IL, USA.

PMID: 24639629 PMCID: PMC3945638 DOI: 10.3389/fncel.2014.00068

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP) in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6) show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular trafficking of BDNF-containing dense core vesicles. Here, we show that the selective HDAC6 inhibitor Tubastatin-A increased the velocity of BDNF-YFP vesicles in Mecp2 knockout neurons in both directions by increasing α-tubulin acetylation. Tubastatin-A also restored activity-dependent BDNF release from Mecp2 knockout neurons to levels comparable to those shown by wildtype neurons. These findings demonstrate that a selective HDAC6 inhibitor is a potential pharmacological strategy to reverse cellular and synaptic impairments in RTT resulting from impaired BDNF signaling.

Keywords: Rett syndrome; Tubastatin-A; activity-dependent BDNF release; dense core vesicle; tubulin acetylation

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