Inhibition of Histone Deacetylase 3 Restores Amyloid-β Oligomer-Induced Plasticity Deficit in Hippocampal CA1 Pyramidal Neurons

Abstract

Neurodegenerative diseases such as Alzheimer’s disease (AD) are associated with alterations in epigenetic factors leading to cognitive decline. Histone deacetylase 3 (HDAC3) is a known critical epigenetic negative regulator of learning and memory. In this study, attenuation of long-term potentiation by amyloid-β oligomer, and its reversal by specific HDAC3 inhibitor RGFP966, was performed in rat CA1 pyramidal neurons using whole cell voltage-clamp and field recording techniques. Our findings provide the first evidence that amyloid-β oligomer-induced synaptic plasticity impairment can be prevented by inhibition of HDAC3 enzyme both at the single neuron as well as in a population of neurons, thus identifying HDAC3 as a potential target for ameliorating AD related plasticity impairments.

Keywords

Amyloid-β oligomer epigenetics HDAC3 long-term potentiation RGFP966 synaptic plasticity

INTRODUCTION

Emerging evidence demonstrates that synaptic loss, rather than neurofibrillary tangles and amyloid-β plaques (Aβ), is the pathological signature of cognitive dysfunctions in Alzheimer’s disease (AD) [1 –4]. AD mouse models expressing Aβ oligomers exhibit age-dependent spatial memory impairment and attenuated long-term potentiation (LTP) [5 –7]. The epigenetic role of histone acetyl transferases and histone deacetylases (HDACs) in chromatin structure modification is emerging as a basic and key mechanism during the transcriptional regulation of memory formation [8, 9]. Global imbalance and altered levels of histone acetylation lead to impaired synaptic plasticity and long-term memory [10] and are considered as major pathogenic mechanisms in the progression of several neurodegenerative disorders including AD [9 , 11–13]. Among various classes of HDACs, HDAC3, a class I HDAC, has been identified as a critical negative regulator of long-term memory formation [14].

The emerging field of neuroepigenetics has provided evidence that increasing histone acetylation by specific inhibitors of HDACs is a promising therapeutic approach to counteract AD-related forms of memory decline [15 –19]. The HDAC3 inhibitor RGFP966 used in this study is a highly selective inhibitor with a better blood-brain barrier penetrance [20]. We report here that inhibition of HDAC3 by RGFP966 ameliorates Aβ_1 - 42 oligomer induced LTP impairments in single neurons and in a population of neurons. This is the first study that describes reversal of Aβ-induced LTP attenuation by pharmacological inhibition of HDAC3 at the single neuronal level using the whole-cell voltage-clamp technique. In addition, most of the earlier reports that used HDAC inhibitors in the plasticity studies neither distinguished the cell types nor looked at single excitatory neurons [19 , 32–37]. The observed effect of HDAC inhibition in those studies could have been caused also by the alteration of neuronal excitability, inhibitory system, or contribution of glia. Therefore, it was important to study the effect of HDAC inhibitors on excitatory synaptic transmission at single neuron.

METHODS

Preparation of hippocampal slices for whole-cell voltage-clamp recordings

A protocol for animal use was approved by the Institutional Animal Care and Use Committee (IACUC) of National University of Singapore. All experiments were performed on acute transverse hippocampal slices from 4-week-old male Wistar rats (60 slices from 37 rats). CO₂ was used for anesthetization and brains were rapidly removed after decapitation and placed in ice-cold oxygenated artificial cerebrospinal fluid (ACSF) containing the following (in mM): 206 sucrose, 2.8 KCl, 1 MgCl₂, 1 CaCl₂, 2 MgSO₄, NaH₂PO₄, NaHCO₃, 10 glucose, and 0.4 ascorbic acid, pH 7.3, 95% O₂/5% CO₂. Slices were cut at a thickness of 350 μm using a vibratome (VT1200S; Leica Biosystems) and immediately transferred to an incubation chamber filled with ACSF containing the following (in mM): 124 NaCl, 3.7 KCl, 1.2 KH₂PO₄, 1 MgSO₄.7H₂O, 2.5 CaCl₂·2H₂O, 24.6 NaHCO₃, and 10 glucose, pH 7.3, equilibrated with to 95% O₂ and 5% CO₂ as reported previously [21]. Slices were allowed to recover at 32°C for 1 h and were then maintained at room temperature. Picrotoxin (100 μM) was added to the bath medium in all experiments to block the action of GABA receptors [22].

Preparation of hippocampal slices for field recording studies

A total of 28 hippocampal slices from 14 male Wistar rats (5–7 weeks old) were analyzed. Animals were maintained on a 12/12 h light dark cycle, with food and water available ad libitum. The rats were decapitated after anesthetization using CO₂ and the brains were quickly transferred into cold (2–4°C) ACSF. The ACSF contained the following (in mM): 124 NaCl, 3.7 KCl, 1.0 MgSO₄·7H₂O, 2.5 CaCl₂·2H₂O, 1.2 KH₂PO4, 24.6 NaHCO₃, and 10 D-glucose, equilibrated with 95% O₂–5% CO₂ (carbogen; total consumption 16 L/h). From each rat, 8–10 transverse slices from the right hippocampus (400 μm-thick) were prepared using a tissue chopper. The slices were incubated at 32°C in an interface chamber (Scientific System Design) with ACSF flow rate of 1 mL/min.

Recordings and stimulations were carried out using the procedures described in [23]. Late-LTP was induced using three stimulus trains of 100 pulses (“strong” tetanus [STET], 100 Hz; duration, 0.2 ms/polarity; inter-train interval, 10 min) [23, 24].

Pharmacology

The HDAC3 inhibitor, RGFP966 (20 μM; Abcam), Aβ_1 - 42, Aβ_42 - 1 oligomer (200 nM; Sigma), Picrotoxin (100 μM; Sigma), and emetine dihydrochloride hydrate (20 μM; Sigma) were used according to manufacturer’s instructions, unless otherwise specified. The concentration of RGFP966 was determined based on the earlier publication [25]. The authors have reported that the IC50 of pimelicdiphenylamides (such as RGFP966) can vary depending on various factors such as pre-incubation time [25]. Specifically, it has been shown that reducing the pre-incubation time resulted in a significant rise of IC50. All drugs were prepared as stock solutions and stored at –20°C and kept for a maximum of one week. Stocks were diluted to the required working concentration in ACSF immediately prior to the experiment. The final DMSO concentration was kept below 0.1% to avoid effects on basal synaptic responses [23].

Electrophysiology for whole-cell voltage-clamp recordings

Whole-cell voltage-clamp recordings of evoked excitatory postsynaptic currents (EPSCs) were generated from the soma of visually identified pyramidal neurons located within the CA1 region of the hippocampus. Patch pipettes (5–7 MΩ) were filled with internal solution containing (in mM): 135 CsMeSO₃, 8 NaCl, 10 HEPES, 0.25 EGTA, 2Mg₂ATP, 0.3Na₃GTP, 0.1 spermine, 7 phosphocreatine, and 5QX-314 (pH 7.3). Series (access) resistance was observed throughout each experiment and was within the range of 15–35 MΩ. The access resistance, membrane resistance, and membrane capacitance was monitored during the experiment to ensure the stability and the health of cells. Recordings were considered stable when the membrane resistance, membrane capacitance, and holding current did not change more than 20%. Holding potentials were –70 mV. The triple patch-clamp EPC10 patch-clamp amplifier and software Patchmaster (HEKA Electronics, Lambrecht, Germany) were used for data acquisition. In addition, a CED 1401 analog to digital converter (Cambridge Electronic Design) and a custom-made software program was used to regulate stimulation and to record evoked EPSCs.

Basal synaptic transmission was studied using the patch-clamp technique in the whole-cell configuration as previously described for AD rodent models [26]. EPSCs were evoked by stimulation of Schaffer-collateral fibers in the stratum radiatum (str. rad.) using glass capillary microelectrodes filled with ACSF. Schaffer collateral/commissural projections were stimulated at 0.05 Hz by 200 micro sec voltage pulses generated by an isolated pulse stimulator (Model 2100, AM systems). The stimulation strength (2–5 V) was adjusted to evoke EPSCs with amplitude of approximately 50 pA. Baseline recordings were made for at least 5 min prior to LTP induction. LTP was induced within 10 min after whole-cell break-in by a one second, 100 Hz stimulation burst (high frequency stimulation) synchronized with a depolarization to zero mV for 2 s through the patch-pipette. The slope of EPSCs was measured to analyze the change in synaptic transmission before and after induction of LTP in CA1 pyramidal cells. The EPSC slope values were normalized to the first 5 min of EPSCrecording.

Statistical analysis

The average values of the EPSC slopes (pA/ms) or fEPSP (mV/ms) per time point were analyzed using the Wilcoxon signed rank test when compared within one group, or the Mann-Whitney U-test when data were compared between groups; p < 0.05 was considered statistically significant [27]. Calculated p values for comparisons are presented in Supplementary Tables 1–3.

RESULTS

First we confirmed the stability of evoked EPSC recording for 30 min (Fig. 1B; n = 4) and established that the LTP induction paradigm evoked a robust EPSC potentiation (Fig. 1C, n = 8). Statistically significant EPSC potentiation was observed for the entire recording period after LTP induction. Application of emetine (20 μM) reduced the EPSC potentiation to baseline level (Fig. 1D, n = 7) indicating that EPSC potentiation requires protein synthesis (details of statistical analysis for Fig. 1 are displayed in Supplementary Table 1). Emetine (20 μM) did not have any effect on control baseline potentials (data not shown). Next, to determine the effect of Aβ_1 - 42 oligomer on LTP, Aβ oligomer (200 nM) was bath applied for 20 min prior to LTP induction. A similar initial level of EPSC potentiation was observed as for the drug free control (Fig. 1C); however, the potentiation did not persist and declined to baseline level within 15 min (Fig. 2A, n = 8). This observation is consistent with previous reports [7, 27], where it was shown that similar Aβ oligomers concentrations impair potentiation of synaptic transmission within 20 min after its induction. Moreover, treatment with the control peptide, which is the reverse sequence of Aβ_1 - 42, had no effect on LTP (Fig. 2B,n = 7).

To determine the role of HDAC3 on LTP, we utilized the HDAC3 specific inhibitor RGFP966 [20]. Notably, when RGFP966 (20 μM) was co-applied with Aβ_1 - 42 oligomer for a total of 30 min, the impairment of LTP maintenance was rescued and resembled that of the control experiments (Fig. 2C, n = 11). Post LTP induction potentials showed statistically significant potentiation up to the end of recording. The same concentration of RGFP966 did not show any visible effects on control-LTP (Supplementary Fig. 1, n = 6). Lower concentrations of RGFP966 (5–10 μM) were unable to rescue LTP maintenance (data not shown). The amelioration of LTP was prevented when RGFP966 was co-applied with emetine (Fig. 2D, n = 6). These data suggests that the enhancement of histone acetylation reverses the Aβ_1 - 42 oligomer induced LTP impairment in a protein synthesis-dependent manner. The complete details of statistical analysis for Fig. 2 are displayed in Supplementary Table 2.

To verify whether RGFP966 exhibits non-specific effect on basal synaptic transmission at the concentration used, the slices were treated with the drug for 30 min and EPSCs were recorded (Fig. 2E, n = 5). No significant effect on basal synaptic transmission was observed. The bar graph (Fig. 2F) represents EPSC potentiation of control LTP (Fig. 1C), LTP with Aβ_1 - 42 oligomer (Fig. 2A) and LTP with Aβ_1 - 42 oligomer along with RGFP966 (Fig. 2C).

Since Aβ_1 - 42 oligomer-induced impairments in LTP can be restored in single neuron by HDAC3 inhibition, it was tested whether it can be achieved in a population of neurons. Aβ_1 - 42 oligomer-impaired LTP in hippocampal slices was investigated using field recording techniques by employing the two input model (Fig. 3A). In a control set of experiments, after a stable baseline of 60 min in synaptic input S1 and S2, we induced LTP in S1, that lasted at least 240 min (Fig. 3B, filled circles, n = 5). A separate control pathway S2 (Fig. 3B, open circles) remained stable at baseline values. To investigate the role of Aβ oligomers during the induction of late-LTP, a stable baseline of 40 min was recorded in S1 and S2 after which Aβ_1 - 42 (200 nM) was bath applied for 20 min prior to STET (Fig. 3C, filled circles, n = 6). Consistent with Fig. 2A, late-LTP was prevented without affecting the control input S2 (Fig. 3C, open circles), which remained stable at baseline levels for the entire recording period of 240 min. Similar treatment with the control peptide Aβ_42 - 1 did not affect the maintenance of late-LTP (Fig. 3D, n = 5). Consistent with Fig. 2C, application of RGFP966 (20 μM) along with the Aβ_1 - 42 oligomer for 20 min before STET and then RGFP966 alone in the bath for the next 30 min rescued the late-LTP impairment caused by Aβ oligomers (Fig. 3E, filled circles, n = 6). The experimental design for Fig. 3F was similar to Fig. 3E but with the exception that 20 μM emetine was co-applied with RGFP966. Here, amelioration of late-LTP was prevented when HDAC3i was co-applied with emetine (Fig. 3F, n = 6). The complete details of statistical analysis for Fig. 3 are displayed in Supplementary Table 3. In short, these experiments suggest that the enhancement of acetylation recovers Aβ_1 - 42 oligomer impaired LTP in a protein synthesis dependent manner at both single and at a population of neurons in the hippocampal CA1 pyramidalneurons.

DISCUSSION

The results presented here clearly demonstrate that RGFP966, a selective HDAC3 inhibitor, rescues Aβ oligomer-induced impairments in LTP. This is the first study that shows reversal of Aβ-induced LTP attenuation by HDAC inhibition investigated at the single neuron level. The reversal of Aβ oligomer-induced plasticity impairments by RGFP966 is protein synthesis dependent. The rapid effect of emetine on the maintenance of LTP in whole cell condition is identical to the previous findings from the CA1 region of hippocampus [28].

It is known that reduced histone acetylation occurs in various neurodegenerative disorders including AD [29 –32]. Thus a strategy to ameliorate the impaired memory formation in AD patients could be to increase the histone acetylation by inhibition of HDAC. Indeed, it has been reported earlier that HDAC inhibitors increase global acetylation via chromatin modification resulting in reversal of memory impairments [19 , 33–38]. It has also been reported that focal deletion of HDAC3 in the dorsal CA1 region leads to increased histone acetylation, gene expression, and long-term memory [14]. A recent study reported that HDAC3 inhibition by RGFP966 had only a minimal or no effect on synaptogenesis and spine density and did not rescue memory in an animal model of AD [39] highlighting that the class I HDAC inhibitor’s efficiency for memory promotion may depend on isoform selectivity and pathological states of the synaptic networks [39]. However, we provide the evidence that HDAC3 inhibitor is effective at single neuron/synapse level to re-establish plasticity, which was impaired by Aβ oligomers. This finding is an important step in understanding the properties of AD pathology at synaptic level because AD has been proposed as a disease of synaptic failure [1, 2].

The ‘Molecular brake pad hypothesis’ proposes that HDACs and their associated co-repressor complexes act in neurons to temporarily block gene activation required for long-term memory formation [40]. Thus, deletion or inhibition of specific HDACs would lead to a ‘permissive’ chromatin state resulting in transcription-dependent long-term memory processes [14 , 37]. The CREB-binding protein (CBP) can acetylate specific CREB lysine residues resulting in transcriptional activation [35]. We therefore hypothesize that HDAC3 inhibition rescues memory processes by activation of key genes regulated by the CREB:CBP transcriptional complex [14 , 42]. Histone acetylation mediated reversal of the hippocampus-dependent memory deficit could act via up regulation of CREB target genes such as Nr4a1 and Nr4a2 [33]. Moreover, RGFP966 reduced HDAC3 repression of c-fos and Nr4a2, and promoted acetylation of H4K8 and H3K14, two sites implicated in memory processes [20]. Alternately, activation of nuclear factor kappa B (NFκB) pathway may play a role in maintaining plasticity, indeed we have shown recently that HDAC3 inhibition re-establishes plasticity in aged neural networks by activating NFκB [24].

The specificity of most of the HDAC inhibitors is a major issue because of the similarities in the catalytic site of various HDAC enzymes. Recent studies have demonstrated that RGFP966 is 200-fold more selective for HDAC3 than other existing specific HDAC inhibitors, and RGFP966 did not show any activity against other HDACs [20 , 43]. Furthermore, various in vivo and in vitro studies have demonstrated a high selectivity for RGFP966 toward HDAC3 [15 , 45], making the use of RGFP966 as a selective inhibitor of HDAC3 justified.

These results highlight RGFP966 as a promising drug to target pathological histone-acetylation, even at the single neuron level. Future studies involving combined neuropharmacological, genetic, and electrophysiological approaches are warranted to demonstrate HDAC3 inhibition mediated restoration of Aβ-induced plasticity deficit.

Footnotes

ACKNOWLEDGMENTS

We are grateful to Dr. Megan Finch-Edmondson for copy editing the manuscript, Dr. Ong Wei-Yi, Ms. Radha Raghuraman, Mr. Mahesh Shivarama Shetty, and Dr. Sheeja Navakkode for the helpful comments. We thank Suma Gopinadhan and Neo Sin Hui for their excellent technical assistance. S.S is supported by National Medical Research Council Collaborative Research Grant (NMRC-CBRG-0041/2013), Ministry of Education Academic Research Funding (MOE AcRF- Tier 1-T1-2012 Oct-02) and NUS-Strategic and Aspiration Research Funds. T.B is supported by NSFC (31320103906, 31271197).

Authors’ disclosures available online ().

Appendix

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