The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons

Yamakawa, Hidekuni; Cheng, Jemmie; Penney, Jay; Gao, Fan; Rueda, Richard; Wang, Jun; Yamakawa, Satoko; Kritskiy, Oleg; Gjoneska, Elizabeta; Tsai, Li‐Huei

doi:10.1016/j.celrep.2017.07.044

Cited by 80 publications

(63 citation statements)

References 55 publications

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“…Indeed, how multiple HDAC isoforms affect learning and memory has been elucidated. For example, HDAC2, negatively regulates hippocampal-dependent memory (Guan et al, 2009;Yamakawa et al, 2017). Recently, it was found that the enzyme acetyl-CoA synthetase 2 (ACSS2) binds to promoters of neuronal activity and memory-related genes where it locally catalyzes the production of acetyl coenzyme A (Acetyl CoA) from acetate, coenzyme A (CoA), and ATP.…”

Section: Discussionmentioning

confidence: 99%

Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF)

Hayek¹,

Khalifeh²,

Zibara³

et al. 2019

J. Neurosci.

289

317

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Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate Bdnf expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted.It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing Bdnf expression and signaling in the hippocampus. Understanding how exercise induces Bdnf and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in Bdnf expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill."

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Section: Discussionmentioning

confidence: 99%

Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF)

Hayek¹,

Khalifeh²,

Zibara³

et al. 2019

J. Neurosci.

289

317

View full text Add to dashboard Cite

show abstract

“…Previous work using a murine hippocampal model demonstrates a role for histone acetylation and subsequent expression of neuronal genes involved in memory formation (Mews et al 2017). In mammals, Sp3 has been shown to recruit HDAC2 to synaptic specific genes, without interfering in other HDAC2 gene targets (Yamakawa et al 2017(Yamakawa et al , 1319(Yamakawa et al -1334. Together, these findings suggest the presence of specific recruitment factors that dictate the acetylation state of cell-type specific genes.…”

Section: Discussionmentioning

confidence: 99%

Machine learning analysis identifiesDrosophila Grunge/Atrophinas an important learning and memory gene required for memory retention and social learning

Kacsoh

Greene

Bosco

2017

Preprint

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High throughput experiments are becoming increasingly common, and scientists must balance hypothesis driven experiments with genome wide data acquisition. We sought to predict novel genes involved in Drosophila learning and long-term memory from existing public high-throughput data. We performed an analysis using PILGRM, which analyzes public gene expression compendia using machine learning. We evaluated the top prediction alongside genes involved in learning and memory in IMP, an interface for functional relationship networks. We identified Grunge/Atrophin (Gug/Atro), a transcriptional repressor, histone deacetylase, as our top candidate. We find, through multiple, distinct assays, that Gug has an active role as a modulator of memory retention in the fly and its function is required in the adult mushroom body. Depletion of Gug specifically in neurons of the adult mushroom body, after cell division and neuronal development is complete, suggests that Gug function is important for memory retention through regulation of neuronal activity, and not by altering neurodevelopment. Our study provides a previously uncharacterized role for Gug as a possible regulator of neuronal plasticity at the interface of memory retention and memory extinction.

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“…We identify one such gene, Endo-B1, for which the neuronspecific isoforms are selectively decreased in AD (37). It remains to be determined whether HDAC2 regulates Endo-B1b/c levels through transcriptional repression as demonstrated for the regulation of synaptic proteins by HDAC2 (15,40). Our preliminary experiments demonstrate that HDAC2 knockdown in cultured neurons increases levels of mRNA for both neuron-specific (Endo-B1b and Endo-B1c) and ubiquitously expressed (Endo-B1a) isoforms (unpublished observation).…”

Section: Hdac2 Regulates Endo-b1 Expression and Aβ Toxicitymentioning

confidence: 94%

Neuronal susceptibility to beta‐amyloid toxicity and ischemic injury involves histone deacetylase‐2 regulation of endophilin‐B1

Wang

Kinoshita

et al. 2018

Brain Pathology

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Histone deacetylases (HDACs) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC2 is highly expressed in adult brain, and HDAC2 levels are elevated in Alzheimer's disease (AD) brain. We previously reported that neuron-specific splice isoforms of Endophilin-B1 (Endo-B1) promote neuronal survival, but are reduced in human AD brain and mouse models of AD and stroke. Here, we demonstrate that HDAC2 suppresses Endo-B1 expression. HDAC2 knockdown or knockout enhances expression of Endo-B1. Conversely, HDAC2 overexpression decreases Endo-B1 expression. We also demonstrate that neurons exposed to beta-amyloid increase HDAC2 and reduce histone H3 acetylation while HDAC2 knockdown prevents Aβ induced loss of histone H3 acetylation, mitochondrial dysfunction, caspase-3 activation, and neuronal death. The protective effect of HDAC2 knockdown was abrogated by Endo-B1 shRNA and in Endo-B1-null neurons, suggesting that HDAC2-induced neurotoxicity is mediated through suppression of Endo-B1. HDAC2 overexpression also modulates neuronal expression of mitofusin2 (Mfn2) and mitochondrial fission factor (MFF), recapitulating the pattern of change observed in AD. HDAC2 knockout mice demonstrate reduced injury in the middle cerebral artery occlusion with reperfusion (MCAO/R) model of cerebral ischemia demonstrating enhanced neuronal survival, minimized loss of Endo-B1, and normalized expression of Mfn2. These findings support the hypothesis that HDAC2 represses Endo-B1, sensitizing neurons to mitochondrial dysfunction and cell death in stroke and AD.

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The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons

Cited by 80 publications

References 55 publications

Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF)

Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF)

Machine learning analysis identifiesDrosophila Grunge/Atrophinas an important learning and memory gene required for memory retention and social learning

Neuronal susceptibility to beta‐amyloid toxicity and ischemic injury involves histone deacetylase‐2 regulation of endophilin‐B1

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