Disruption of MET Receptor Tyrosine Kinase,an Autism Risk Factor,Impairs Developmental Synaptic Plasticity in the Hippocampus

As more genes conferring risks to neurodevelopmental disorders are identified, translating these genetic risk factors into biological mechanisms that impact the trajectory of the developing brain is a critical next step. Here, we report that disrupted signaling mediated MET receptor tyrosine kinase (RTK), an established risk factor for autism spectrum disorders, in the developing hippocampus glutamatergic circuit leads to profound deficits in neural development, synaptic transmission, and plasticity. In cultured hippocampus slices prepared from neonatal mice, pharmacological inhibition of MET kinase activity suppresses dendritic arborization and disrupts normal dendritic spine development. In addition, single‐neuron knockdown (RNAi) or overexpression of Met in the developing hippocampal CA1 neurons leads to alterations, opposite in nature, in basal synaptic transmission and long‐term plasticity. In forebrain‐specific Met conditional knockout mice (Met^fx/fx;emx1^cre), an enhanced long‐term potentiation (LTP) and long‐term depression (LTD) were observed at early developmental stages (P12–14) at the Schaffer collateral to CA1 synapses compared with wild‐type littermates. In contrast, LTP and LTD were markedly reduced at young adult stage (P56–70) during which wild‐type mice show robust LTP and LTD. The altered trajectory of synaptic plasticity revealed by this study indicate that temporally regulated MET signaling as an intrinsic, cell autonomous, and pleiotropic mechanism not only critical for neuronal growth and functional maturation, but also for the timing of synaptic plasticity during forebrain glutamatergic circuits development.     

SMRT‐mediated co‐shuttling enables export of class IIa HDACs independent of their CaM kinase phosphorylation sites

The Class IIa histone deacetylases (HDAC)4 and HDAC5 play a role in neuronal survival and behavioral adaptation in the CNS. Phosphorylation at 2/3 N‐terminal sites promote their nuclear export. We investigated whether non‐canonical signaling routes to Class IIa HDAC export exist because of their association with the co‐repressor Silencing Mediator Of Retinoic And Thyroid Hormone Receptors (SMRT). We found that, while HDAC5 and HDAC4 mutants lacking their N‐terminal phosphorylation sites (HDAC4^MUT, HDAC5^MUT) are constitutively nuclear, co‐expression with SMRT renders them exportable by signals that trigger SMRT export, such as synaptic activity, HDAC inhibition, and Brain Derived Neurotrophic Factor (BDNF) signaling. We found that SMRT's repression domain 3 (RD3) is critical for co‐shuttling of HDAC5^MUT, consistent with the role for this domain in Class IIa HDAC association. In the context of BDNF signaling, we found that HDAC5^WT, which was more cytoplasmic than HDAC5^MUT, accumulated in the nucleus after BDNF treatment. However, co‐expression of SMRT blocked BDNF‐induced HDAC5^WT import in a RD3‐dependent manner. In effect, SMRT‐mediated HDAC5^WT export was opposing the BDNF‐induced HDAC5 nuclear accumulation observed in SMRT's absence. Thus, SMRT's presence may render Class IIa HDACs exportable by a wider range of signals than those which simply promote direct phosphorylation.     

NMDA receptors on zebrafish Mauthner cells require CaMKII‐α for normal development

Calcium/calmodulin dependent protein kinase 2 (CaMKII) is a multifunctional protein that is highly enriched in the synapse. It plays important roles in neuronal functions such as synaptic plasticity, synaptogenesis, and neural development. Gene duplication in zebrafish has resulted in the occurrence of seven CaMKII genes (camk2a, camk2b1, camk2b2, camk2g1, camk2g2, camk2d1, and camk2d2) that are developmentally expressed. In this study, we used single cell, real‐time quantitative PCR to investigate the expression of CaMKII genes in individual Mauthner cells (M‐cells) of 2 days post fertilization (dpf) zebrafish embryos. We found that out of seven different CaMKII genes, only the mRNA for CaMKII‐α was expressed in the M‐cell at detectable levels, while all other isoforms were undetectable. Morpholino knockdown of CaMKII‐α had no significant effect on AMPA synaptic currents (mEPSCs) but decreased the amplitude of NMDA mEPSCs. NMDA events exhibited a biexponential decay with τ_fast ≈ 30 ms and τ_slow ≈ 300 ms. Knockdown of CaMKII‐α specifically reduced the amplitude of the slow component of the NMDA‐mediated currents (mEPSCs), without affecting the fast component, the frequency, or the kinetics of the mEPSCs. Immunolabelling of the M‐cell showed increased dendritic arborizations in the morphants compared with controls, and knockdown of CaMKII‐α altered locomotor behaviors of touch responses. These results suggest that CaMKII‐α is present in embryonic M‐cells and that it plays a role in the normal development of excitatory synapses. Our findings pave the way for determining the function of specific CaMKII isoforms during the early stages of M‐cell development. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 145–162, 2015     

HDACi protects against vascular cognitive impairment from CCH injury via induction of BDNF-related AMPA receptor activation

We previously showed a hydroxamic acid-based histone deacetylase inhibitor (HDACi), compound 13, provides neuroprotection against chronic cerebral hypoperfusion (CCH) both in vitro under oxygen-glucose deprivation (OGD) conditions and in vivo under bilateral common carotid artery occlusion (BCCAO) conditions. Intriguingly, the protective effect of this HDACi is via H3K14 or H4K5 acetylation–mediated differential BDNF isoform activation. BDNF is involved in cell proliferation and differentiation in development, synaptic plasticity and in learning and memory related with receptors or synaptic proteins. B6 mice underwent BCCAO and were randomized into 4 groups; a sham without BCCAO (sham), BCCAO mice injected with DMSO (DMSO), mice injected with HDACi-compound 13 (compound 13) and mice injected with suberoylanilide hydroxamic acid (SAHA). The cortex and hippocampus of mice were harvested at 3 months after BCCAO, and levels of BDNF, AMPA receptor and dopamine receptors (D1, D2 and D3) were studied using Western blotting analysis or immunohistochemistry. We found that the AMPA receptor plays a key role in the molecular mechanism of this process by modulating HDAC. This protective effect of HDACi may be through BDNF; therefore, activation of this downstream signalling molecule, for example by AMPA receptors, could be a therapeutic target or intervention applied under CCH conditions.     

NMDAR‐dependent Argonaute 2 phosphorylation regulates miRNA activity and dendritic spine plasticity

MicroRNAs (miRNAs) repress translation of target mRNAs by associating with Argonaute (Ago) proteins to form the RNA‐induced silencing complex (RISC), underpinning a powerful mechanism for fine‐tuning protein expression. Specific miRNAs are required for NMDA receptor (NMDAR)‐dependent synaptic plasticity by modulating the translation of proteins involved in dendritic spine morphogenesis or synaptic transmission. However, it is unknown how NMDAR stimulation stimulates RISC activity to rapidly repress translation of synaptic proteins. We show that NMDAR stimulation transiently increases Akt‐dependent phosphorylation of Ago2 at S387, which causes an increase in binding to GW182 and a rapid increase in translational repression of LIMK1 via miR‐134. Furthermore, NMDAR‐dependent down‐regulation of endogenous LIMK1 translation in dendrites and dendritic spine shrinkage requires phospho‐regulation of Ago2 at S387. AMPAR trafficking and hippocampal LTD do not involve S387 phosphorylation, defining this mechanism as a specific pathway for structural plasticity. This work defines a novel mechanism for the rapid transduction of NMDAR stimulation into miRNA‐mediated translational repression to control dendritic spine morphology.     

Synaptotagmin‐1 promotes the formation of axonal filopodia and branches along the developing axons of forebrain neurons

Synaptotagmin‐1 (syt1) is a Ca²⁺‐binding protein that functions in regulation of synaptic vesicle exocytosis at the synapse. Syt1 is expressed in many types of neurons well before synaptogenesis begins both in vivo and in vitro. To determine if expression of syt1 has a functional role in neuronal development before synapse formation, we examined the effects of syt1 overexpression and knockdown on the growth and branching of the axons of cultured primary embryonic day 8 chicken forebrain neurons. In vivo these neurons express syt1, and most have not yet extended axons. We present evidence that syt1 plays a role in regulating axon branching, while not regulating overall axon length. To study the effects of overexpression of syt1, we used adenovirus‐mediated infection to introduce a syt1‐YFP construct, or control GFP construct, into neurons. Syt1 levels were reduced using RNA interference. Overexpression of syt1 increased the formation of axonal filopodia and branches. Conversely, knockdown of syt1 decreased the number of axonal filopodia and branches. Time‐lapse analysis of filopodial dynamics in syt1‐overexpressing cells demonstrated that elevation of syt1 levels increased both the frequency of filopodial initiation and their lifespan. Taken together these data indicate that syt1 regulates the formation of axonal filopodia and branches before engaging in its conventional functions at the synapse. © 2011 Wiley Periodicals, Inc. Develop Neurobiol, 2013     

Histone deacetylase mediates the decrease in drebrin cluster density induced by amyloid beta oligomers

Dendritic spine defects are found in a number of cognitive disorders, including Alzheimer’s disease (AD). Amyloid beta (Aβ) toxicity is mediated not only by the fibrillar form of the protein, but also by the soluble oligomers (Aβ-derived diffusible ligands, ADDLs). Drebrin is an actin-binding protein that is located at mature dendritic spines. Because drebrin expression is decreased in AD brains and in cultured neurons exposed to Aβ, it is thought that drebrin is closely associated with cognitive functions. Recent studies show that histone deacetylase (HDAC) activity is elevated in the AD mouse model, and that memory impairments in these animals can be ameliorated by HDAC inhibitors. In addition, spine loss and memory impairment in HDAC2 over-expressing mice are ameliorated by chronic HDAC inhibitor treatment. Therefore, we hypothesized that the regulation of histone acetylation/deacetylation is critical to synaptic functioning. In this study, we examined the relationship between HDAC activity and synaptic defects induced by ADDLs using an HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA). We show that ADDLs reduce the cluster density of drebrin along dendrites without reducing drebrin expression. SAHA markedly increased the acetylation of histone proteins, and it simultaneously attenuated the ADDL-induced decrease in drebrin cluster density. In comparison, SAHA treatment did not affect the density of drebrin clusters or dendritic protrusions in control neurons. Therefore, SAHA likely inhibits ADDL-induced drebrin loss from dendritic spines by stabilizing drebrin in these structures, rather than by increasing drebrin clusters or dendritic protrusions. Taken together, our findings suggest that HDAC is involved in ADDL-induced synaptic defects, and that the regulation of histone acetylation plays an important role in modulating actin cytoskeletal dynamics in dendritic spines under cellular stress conditions, such as ADDL exposure.     

Early life stress‐induced histone acetylations correlate with activation of the synaptic plasticity genes Arc and Egr1 in the mouse hippocampus

Early life stress (ELS) programs the developing organism and influences the development of brain and behavior. We tested the hypothesis that ELS‐induced histone acetylations might alter the expression of synaptic plasticity genes that are critically involved in the establishment of limbic brain circuits. Maternal separation (MS) from postnatal day 14–16 was applied as ELS and two immediate early genes underlying experience‐induced synaptic plasticity, Arc and early growth response 1 (Egr1) were analyzed. We show here that repeated ELS induces a rapid increase of Arc and Egr1 in the mouse hippocampus. Furthermore, immunoblotting revealed that these changes are paralleled by histone modifications, reflected by increased acetylation levels of H3 and H4. Most importantly, using native Chromatin immunoprecipitation quantitative PCR (nChIP‐qPCR), we show for the first time a correlation between elevated histone acetylation and increased Arc and Egr1 expression in response to ELS. These rapid epigenetic changes are paralleled by increases of dendritic complexity and spine number of hippocampal CA3 pyramidal neurons in ELS animals at weaning age. Our results are in line with our working hypothesis that ELS induces activation of synaptic plasticity genes, mediated by epigenetic mechanisms. These events are assumed to represent early steps in the adaption of neuronal networks to a stressful environment.     

Magnetic stimulation modulates structural synaptic plasticity and regulates BDNF–TrkB signal pathway in cultured hippocampal neurons

Repetitive transcranial magnetic stimulation (rTMS) is a neuropsychiatric tool that can be used to investigate the neurobiology of learning and cognitive function. Few studies have examined the effects of low frequency (?1 Hz) magnetic stimulation (MS) on structural synaptic plasticity of neurons in vitro, thus, the current study examined its effects on hippocampal neuron and synapse morphology, as well as synaptic protein markers and signaling pathways. Similarly, both intensities of low frequency magnetic stimulation (1 Hz) activated brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) pathways, including the pathways for mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and for phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt). Specifically, low intensity magnetic stimulation (LIMS, 1.14 Tesla, 1 Hz) promoted more extensive dendritic and axonal arborization, as well as increasing synapses density, thickening PSD (post synaptic density) and upregulation of synaptophysin (SYN), growth associated protein 43 (GAP43) and post synaptic density 95 (PSD95). Conversely, high intensity magnetic stimulation (HIMS, 1.55 Tesla, 1 Hz) appeared to be detrimental, reducing dendritic and axonal arborization and causing apparent structural damage, including thinning of PSD, less synapses and disordered synaptic structure, as well as upregulation of GAP43 and PSD95, possibly for their ability to mitigate dysfunction. In conclusion, we infers that low frequency magnetic stimulation participates in regulating structural synaptic plasticity of hippocampal neurons via the activation of BDNF–TrkB signaling pathways.     

Lrig1 is a cell‐intrinsic modulator of hippocampal dendrite complexity and BDNF signaling

Even though many extracellular factors have been identified as promoters of general dendritic growth and branching, little is known about the cell‐intrinsic modulators that allow neurons to sculpt distinctive patterns of dendrite arborization. Here, we identify Lrig1, a nervous system‐enriched LRR protein, as a key physiological regulator of dendrite complexity of hippocampal pyramidal neurons. Lrig1‐deficient mice display morphological changes in proximal dendrite arborization and defects in social interaction. Specifically, knockdown of Lrig1 enhances both primary dendrite formation and proximal dendritic branching of hippocampal neurons, two phenotypes that resemble the effect of BDNF on these neurons. In addition, we show that Lrig1 physically interacts with TrkB and attenuates BDNF signaling. Gain and loss of function assays indicate that Lrig1 restricts BDNF‐induced dendrite morphology. Together, our findings reveal a novel and essential role of Lrig1 in regulating morphogenic events that shape the hippocampal circuits and establish that the assembly of TrkB with Lrig1 represents a key mechanism for understanding how specific neuronal populations expand the repertoire of responses to BDNF during brain development.     

From modulator to mediator: rapid effects of BDNF on ion channels

Neurotrophins (NTs) are {?AUTHOR} a family of structurally related, secreted proteins that regulate the survival, differentiation and maintenance of function of different populations of peripheral and central neurons. 1 , 2 Among these, BDNF (brain‐derived neurotrophic factor) has drawn considerable interest because both its synthesis and secretion are increased by physiological levels of activity, indicating a unique role of this neurotrophin in coupling neuronal activity to structural and functional properties of neuronal circuits. In addition to its classical neurotrophic effects, which are evident within hours or days and which usually result from changes in cellular gene expression, BDNF exerts acute effects on synaptic transmission and is involved in the induction of long‐term potentiation. Many of these rapid effects of BDNF are mediated by its modulation of ion channel properties following TrkB‐mediated activation of intracellular second messenger cascades and protein phosphorylation. However, recent reports have shown that BDNF not only acts as a modulator of ion channels, but can also directly and rapidly gate a Na⁺ channel, thereby assigning BDNF the properties of a classical excitatory transmitter. Thus, BDNF, in addition its role as a potent neuromodulator, emerges as an excitatory transmitter‐like substance which acutely controls resting membrane potential, neuronal excitability, synaptic transmission and participates in the induction of synaptic plasticity. BioEssays 26:1185–1194, 2004. © 2004 Wiley Periodicals, Inc.     

Involvement of HDAC1 in E-cadherin expression in prostate cancer cells; its implication for cell motility and invasion

In this study, we investigate the molecular mechanism by which histone deacetylase (HDAC) inhibitors exert anti-invasiveness effect against prostate cancer cells. We first evaluate the growth inhibition effect of HDAC inhibitors in prostate cancer cells, which is accompanied by induction of p21^WAF1 expression and accumulation of acetylated histones. And we found that the migration and invasion of prostate cancer cells is strongly inhibited by treatment with HDAC inhibitors. In parallel, E-cadherin level is highly up-regulated in HDAC inhibitor-treated prostate cancer cells. And siRNA knockdown of E-cadherin significantly diminishes the anti-invasion effect of HDAC inhibitors, indicating that E-cadherin overexpression is one of possible mechanism for anti-invasion effect of HDAC inhibitors. Furthermore, specific downregulation of HDAC1, but not HDAC2, causes E-cadherin expression and subsequent inhibition of cell motility and invasion. Collectively, our data demonstrate that HDAC1 is a major repressive enzyme for E-cadherin expression as well as HDAC inhibitor-mediated anti-invasiveness.     

The regulatory role of c‐MYC on HDAC2 and PcG expression in human multipotent stem cells

Myelocytomatosis oncogene (c‐MYC) is a well‐known nuclear oncoprotein having multiple functions in cell proliferation, apoptosis and cellular transformation. Chromosomal modification is also important to the differentiation and growth of stem cells. Histone deacethylase (HDAC) and polycomb group (PcG) family genes are well‐known chromosomal modification genes. The aim of this study was to elucidate the role of c‐MYC in the expression of chromosomal modification via the HDAC family genes in human mesenchymal stem cells (hMSCs). To achieve this goal, c‐MYC expression was modified by gene knockdown and overexpression via lentivirus vector. Using the modified c‐MYC expression, our study was focused on cell proliferation, differentiation and cell cycle. Furthermore, the relationship of c‐MYC with HDAC2 and PcG genes was also examined. The cell proliferation and differentiation were checked and shown to be dramatically decreased in c‐MYC knocked‐down human umbilical cord blood‐derived MSCs, whereas they were increased in c‐MYC overexpressing cells. Similarly, RT‐PCR and Western blotting results revealed that HDAC2 expression was decreased in c‐MYC knocked‐down and increased in c‐MYC overexpressing hMSCs. Database indicates presence of c‐MYC binding motif in HDAC2 promoter region, which was confirmed by chromatin immunoprecipitation assay. The influence of c‐MYC and HDAC2 on PcG expression was confirmed. This might indicate the regulatory role of c‐MYC over HDAC2 and PcG genes. c‐MYCs’ regulatory role over HDAC2 was also confirmed in human adipose tissue‐derived MSCs and bone‐marrow derived MSCs. From this finding, it can be concluded that c‐MYC plays a vital role in cell proliferation and differentiation via chromosomal modification.     

Chemical Inhibition of Histone Deacetylases 1 and 2 Induces Fetal Hemoglobin through Activation of GATA2

Therapeutic intervention aimed at reactivation of fetal hemoglobin protein (HbF) is a promising approach for ameliorating sickle cell disease (SCD) and β-thalassemia. Previous studies showed genetic knockdown of histone deacetylase (HDAC) 1 or 2 is sufficient to induce HbF. Here we show that ACY-957, a selective chemical inhibitor of HDAC1 and 2 (HDAC1/2), elicits a dose and time dependent induction of γ-globin mRNA (HBG) and HbF in cultured primary cells derived from healthy individuals and sickle cell patients. Gene expression profiling of erythroid progenitors treated with ACY-957 identified global changes in gene expression that were significantly enriched in genes previously shown to be affected by HDAC1 or 2 knockdown. These genes included GATA2, which was induced greater than 3-fold. Lentiviral overexpression of GATA2 in primary erythroid progenitors increased HBG, and reduced adult β-globin mRNA (HBB). Furthermore, knockdown of GATA2 attenuated HBG induction by ACY-957. Chromatin immunoprecipitation and sequencing (ChIP-Seq) of primary erythroid progenitors demonstrated that HDAC1 and 2 occupancy was highly correlated throughout the GATA2 locus and that HDAC1/2 inhibition led to elevated histone acetylation at well-known GATA2 autoregulatory regions. The GATA2 protein itself also showed increased binding at these regions in response to ACY-957 treatment. These data show that chemical inhibition of HDAC1/2 induces HBG and suggest that this effect is mediated, at least in part, by histone acetylation-induced activation of the GATA2 gene.     

Neuropeptide orphanin FQ inhibits dendritic morphogenesis through activation of RhoA

Brain‐derived neurotrophic factor (BDNF) plays a facilitatory role in neuronal development and promotion of differentiation. Mechanisms that oppose BDNF's stimulatory effects create balance and regulate dendritic growth. However, these mechanisms have not been studied. We have focused our studies on the BDNF‐induced neuropeptide OrphaninFQ/ Nociceptin (OFQ); while BDNF is known to enhance synaptic activity, OFQ has opposite effects on activity, learning, and memory. We have now examined whether OFQ provides a balance to the stimulatory effects of BDNF on neuronal differentiation in the hippocampus. Golgi staining in OFQ knockout (KO) mice revealed an increase in primary dendrite length as well as spine density, suggesting that endogenous OFQ inhibits dendritic morphology. We have also used cultured hippocampal neurons to demonstrate that exogenous OFQ has an inhibitory effect on dendritic growth and that the neuropeptide alters the response to BDNF when pre‐administered. To determine if BDNF and OFQ act in a feedback loop, we inhibited the actions of the BDNF and OFQ receptors, TrkB and NOP using ANA‐12 and NOP KO mice respectively but our data suggest that the two factors do not act in a negative feedback loop. We found that the inhibition of dendritic morphology induced by OFQ is via enhanced RhoA activity. Finally, we have evidence that RhoA activation is required for the inhibitory effects of OFQ on dendritic morphology. Our results reveal basic mechanisms by which neurons not only regulate the formation of proper dendritic growth during development but also control plasticity in the mature nervous system. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 769–784, 2013     

Extracellular interactions between GluR2 and N-cadherin in spine regulation

Via its extracellular N-terminal domain (NTD), the AMPA receptor subunit GluR2 promotes the formation and growth of dendritic spines in cultured hippocampal neurons. Here we show that the first N-terminal 92 amino acids of the extracellular domain are necessary and sufficient for GluR2's spine-promoting activity. Moreover, overexpression of this extracellular domain increases the frequency of miniature excitatory postsynaptic currents (mEPSCs). Biochemically, the NTD of GluR2 can interact directly with the cell adhesion molecule N-cadherin, in cis or in trans. N-cadherin-coated beads recruit GluR2 on the surface of hippocampal neurons, and N-cadherin immobilization decreases GluR2 lateral diffusion on the neuronal surface. RNAi knockdown of N-cadherin prevents the enhancing effect of GluR2 on spine morphogenesis and mEPSC frequency. Our data indicate that in hippocampal neurons N-cadherin and GluR2 form a synaptic complex that stimulates presynaptic development and function as well as promoting dendritic spine formation.     

Propofol exposure during early gestation impairs learning and memory in rat offspring by inhibiting the acetylation of histone

Propofol is widely used in clinical practice, including non‐obstetric surgery in pregnant women. Previously, we found that propofol anaesthesia in maternal rats during the third trimester (E18) caused learning and memory impairment to the offspring rats, but how about the exposure during early pregnancy and the underlying mechanisms? Histone acetylation plays an important role in synaptic plasticity. In this study, propofol was administered to the pregnant rats in the early pregnancy (E7). The learning and memory function of the offspring were tested by Morris water maze (MWM) test on post‐natal day 30. Two hours before each MWM trial, histone deacetylase 2 (HDAC2) inhibitor, suberoylanilide hydroxamic acid (SAHA), Senegenin (SEN, traditional Chinese medicine), hippyragranin (HGN) antisense oligonucleotide (HGNA) or vehicle were given to the offspring. The protein levels of HDAC2, acetylated histone 3 (H3) and 4 (H4), cyclic adenosine monophosphate (cAMP) response element‐binding protein (CREB), N‐methyl‐D‐aspartate receptor (NMDAR) 2 subunit B (NR2B), HGN and synaptophysin in offspring's hippocampus were determined by Western blot or immunofluorescence test. It was discovered that infusion with propofol in maternal rats on E7 leads to impairment of learning and memory in offspring, increased the protein levels of HDAC2 and HGN, decreased the levels of acetylated H3 and H4 and phosphorylated CREB, NR2B and synaptophysin. HDAC2 inhibitor SAHA, Senegenin or HGN antisense oligonucleotide reversed all the changes. Thus, present results indicate exposure to propofol during the early gestation impairs offspring's learning and memory via inhibiting histone acetylation. SAHA, Senegenin and HGN antisense oligonucleotide might have therapeutic value for the adverse effect of propofol.