Histone deacetylases in memory and cognition

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Sci. Signal.  09 Dec 2014:
Vol. 7, Issue 355, pp. re12
DOI: 10.1126/scisignal.aaa0069


Over the past 30 years, lysine acetylation of histone and nonhistone proteins has become established as a key modulator of gene expression regulating numerous aspects of cell biology. Neuronal growth and plasticity are no exception; roles for lysine acetylation and deacetylation in brain function and dysfunction continue to be uncovered. Transcriptional programs coupling synaptic activity to changes in gene expression are critical to the plasticity mechanisms underlying higher brain functions. These transcriptional programs can be modulated by changes in histone acetylation, and in many cases, transcription factors and histone-modifying enzymes are recruited together to plasticity-associated genes. Lysine acetylation, catalyzed by lysine acetyltransferases (KATs), generally promotes cognitive performance, whereas the opposing process, catalyzed by histone lysine deacetylases (HDACs), appears to negatively regulate cognition in multiple brain regions. Consistently, mutation or deregulation of different KATs or HDACs contributes to neurological dysfunction and neurodegeneration. HDAC inhibitors have shown promise as a treatment to combat the cognitive decline associated with aging and neurodegenerative disease, as well as to ameliorate the symptoms of depression and posttraumatic stress disorder, among others. In this review, we discuss the evidence for the roles of HDACs in cognitive function as well as in neurological disorders and disease. In particular, we focus on HDAC2, which plays a central role in coupling lysine acetylation to synaptic plasticity and mediates many of the effects of HDAC inhibition in cognition and disease.


Numerous molecular mechanisms act in concert to enact changes in neuronal function in response to diverse inputs. Such synaptic plasticity is critical for learning, memory, and other cognitive processes and is often defective in neurological disease (1). Among the mechanisms required for synaptic plasticity, coordinated changes in gene expression are essential for the consolidation and maintenance of most lasting forms of memory. Indeed, multiple signaling cascades couple transcription factor activation to synaptic activity (2). An additional level of transcriptional regulation occurs in the form of chromatin modification, whereby the accessibility of specific regions of the genome to the transcription machinery can be modulated by local posttranslational modification of histone proteins (3). Acetylation is the best-studied histone modification, and in recent years, it has become clear that histone acetylation dynamics play important roles in various cognitive processes, as well as in multiple neurological disorders. Histone acetylation is tightly regulated by the opposing activities of lysine acetyltransferases (KATs) and histone lysine deacetylases (HDACs). The role of HDACs in brain function and dysfunction forms the focus of this review. Additional histone modifications also participate in cognitive processes and have been reviewed elsewhere (4).

Chromatin and Histone Acetylation

The complex of DNA, proteins, and RNA is referred to as chromatin. The main structural component of chromatin is the nucleosome, which consists of 147 base pairs (bp) of double helical DNA wrapped around a core histone octamer containing two copies each of the histone proteins H2A, H2B, H3, and H4 (5). About 50-bp-long “linker” regions of DNA defined by the linker histone H1 separate individual nucleosomes. The most critical function of organizing DNA into chromatin is to enable the packaging of >1 m of DNA into a single cell’s nucleus; however, chromatin also plays important roles in modulating transcription, DNA repair, and other processes that require intimate access to the DNA.

The strength of the interaction between DNA and histone proteins is affected by a number of different histone posttranslational modifications, occurring at multiple different sites in each histone protein. Often, these modifications occur within the N-terminal histone tails and include phosphorylation, methylation, and acetylation, among others (5). Such modifications can either increase or decrease the affinity of the histone protein for DNA, depending on the particular site and modification, and collectively make up what has been referred to as the “histone code” (6). These modifications can also serve as signals to recruit transcription factors or other molecules to specific locations on the chromatin (5). Acetylation occurs at multiple sites on each histone protein and is most often associated with an “open” chromatin state conducive for promoting gene expression. As such, KAT activity typically promotes gene transcription, whereas HDAC activity typically antagonizes gene transcription.

Three families of KATs use acetyl-coenzyme A to transfer an acetyl group to lysine residues of histone and nonhistone substrates (7). HDACs remove acetyl groups from proteins and are divided into four classes (8). Class I, II, and IV HDACs are zinc-dependent enzymes, whereas class III HDACs (also known as sirtuins) are nicotinamide adenine dinucleotide (NAD)–dependent enzymes. Sirtuins have distinct inhibitor specificities compared to the other classes of HDACs and will not be reviewed here. Class I HDACs (HDACs 1 to 3 and 8) are largely nuclear, but they can also localize to the cytoplasm, whereas class II (HDACs 4 to 7, 9, and 10) and class IV (HDAC11) HDACs are either nucleocytoplasmic shuttling enzymes or primarily cytoplasmic. Notably, class IIa HDACs (HDACs 4, 5, 7, and 9) appear to have very low intrinsic deacetylase activity (9). Like KATs, HDACs can also deacetylate both histone and nonhistone targets.

Three classes of chemical compounds are commonly used as small-molecule inhibitors of zinc-dependent HDACs (10). Carboxylic acids, including sodium butyrate (NaB) and valproic acid (VPA), specifically target class I HDACs. Hydroxamic acids, such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), inhibit both class I and class II HDAC enzymes; however, both compounds target HDACs 1 to 3 and 6 more strongly than HDACs 4 and 5. Finally, ortho-amino anilides, including CI-994, RGFP136, and MS-275, are thought to selectively inhibit class I HDACs. Thus, the HDAC inhibitors used to examine cognitive processes predominantly target class I HDAC enzymes.

Histone Acetylation in Cognition

The first clear evidence of a role for histone acetylation in cognitive processes came from studies of long-term facilitation (LTF) and long-term depression (LTD) in the sea slug, Aplysia californica. Guan and colleagues (11) showed that serotonin, a neurotransmitter that promotes LTF, leads to activation of the transcription factor CREB (cyclic adenosine monophosphate response element–binding protein) and increased expression of target gene C/EBP (CAAT box enhancer binding protein). In parallel with CREB activation, the KAT CBP (CREB-binding protein) was also recruited to the C/EBP promoter where it catalyzed increased histone H3 and H4 acetylation. In contrast, the LTD-inducing neuropeptide FMRFamide led to recruitment of the transcriptional repressor ATF4 (activating transcription factor 4) and a histone deacetylase with homology to HDAC5 to the C/EBP promoter. ATF4/HDAC recruitment displaced CREB/CBP, induced histone deacetylation, and inhibited C/EBP transcription. The authors also found that treatment with the HDAC inhibitor TSA reduced the stimulation required to induce LTF, indicating that HDAC activity can negatively regulate neuronal plasticity. This seminal work suggested that modulation of histone acetylation by the opposing activities of KAT and HDAC enzymes plays an intimate role in at least some forms of lasting synaptic plasticity, and that promoting lysine acetylation has the potential to enhance plasticity.

Mutations disrupting CBP in humans and studies of Cbp mutant mice implicated lysine acetylation in cognitive processes in mammals. Human CBP mutations result in Rubinstein-Taybi syndrome, characterized by physical abnormalities and severe mental disability (12). Consistently, studies of Cbp mutant mice revealed deficits in multiple forms of long-term memory (1316). CBP-dependent synaptic plasticity and memory deficits could, in some cases, be rescued by treatment with the HDAC inhibitors SAHA or TSA, supporting the interplay between acetylation and deacetylation in cognitive function. Short-term memory—including working memory—was not affected by CBP disruption, consistent with the notion that alterations in chromatin acetylation are an important contributor to memory consolidation rather than to short-term plasticity (15, 16).

Further supporting a role for histone acetylation in cognitive function are a number of studies demonstrating that synaptic plasticity and memory-inducing paradigms can promote acetylation in multiple brain regions. In rat hippocampal slices, long-term potentiation (LTP) induction was accompanied by increased H3 acetylation, without change in H4 acetylation (17). Furthermore, fear conditioning, novel object recognition, spatial memory, and fear memory reconsolidation tasks all could variously induce histone acetylation in the rodent hippocampus, cortex, and amygdala (1727). These diverse studies have not consistently reported the effects of synaptic plasticity and memory on the same set of histone marks; however, it is clear that there is specificity in the histone modifications induced during synaptic plasticity. It should be noted that in addition to histone proteins, KATs and HDACs also regulate the acetylation of many nonhistone substrates including transcription factors and RNA polymerase II (28). These nonhistone targets may mediate some of the effects of KAT and HDAC activity on cognitive function, although their contributions remain largely unknown (28). Nevertheless, the above findings strongly implicate the dynamic regulation of histone acetylation as a key modulator of synaptic plasticity and memory formation.

HDAC Inhibitors and Memory Enhancement

Given the histone acetylation changes associated with multiple forms of synaptic plasticity, a role for HDACs in cognition appeared likely. Indeed, numerous studies have found that HDAC inhibitor treatments can promote structural and functional plasticity. Treating mice with NaB, SAHA, or CI-994 increased synapse number, dendritic spine density, and the abundance of multiple synaptic proteins in the hippocampus (2931). Consistently, treatment with TSA, SAHA, or CI-994 either reduced the threshold for LTP induction or increased the magnitude of potentiation in the hippocampus and amygdala (17, 19, 24, 27, 30, 32), although these effects were not always observed (33). Furthermore, multiple HDAC inhibitors improved performance in fear conditioning, object location, novel object recognition, food preference, and spatial memory tasks (2427, 2932, 3438), again with some exceptions (19, 33, 39, 40). Thus, endogenous HDAC activity clearly plays a critical role in cognitive performance and appears to normally restrain both structural and functional synaptic plasticity.

To our knowledge at the time of this review, no impairments in synaptic plasticity or learning after HDAC inhibition have been reported, raising the intriguing possibility that HDAC inhibitors could be used to enhance memory in humans. HDAC inhibitors are used in cancer therapy, and systemic treatment has been relatively well tolerated (41). A major problem with existing HDAC inhibitors, however, is their broad specificity (10). Although it has proven difficult, the development of inhibitors that target specific HDACs would likely reduce the negative side effects that do occur with systemic treatment and could improve the viability of HDAC inhibition as a cognitive therapy.

Which HDACs Are Important in Cognition?

Although numerous different HDAC inhibitors have now been shown to enhance various forms of learning and memory, a critical missing link was the identification of the specific HDAC(s) responsible for mediating such effects. All zinc-dependent HDACs are expressed in the brain including areas that are important for learning and memory (42). As a first step toward understanding the roles of individual HDACs in cognition, Guan et al. (30) generated transgenic mice that either overexpressed or lacked HDAC1 or HDAC2 in the forebrain. These class I HDACs are the most similar of the HDACs on the basis of amino acid sequence and are thought to play redundant roles in many processes (8). The authors found that HDAC2 negatively regulated structural and functional synaptic plasticity, as well as memory formation, in the hippocampus (Fig. 1) (30). They also found that deletion of Hdac2 mimicked the HDAC inhibitor VPA in enhancing synaptic plasticity and memory. Subsequent studies found similar positive effects of deletion or knockdown of HDAC2 on multiple forms of learning and memory as well as LTP (43, 44). Consistently, in hippocampal pyramidal cells, HDAC2 suppresses excitatory inputs and promotes inhibitory inputs in a cell-autonomous manner (44). In each case, these effects were specific to HDAC2; similar manipulations of HDAC1 had no effect on synaptic function, plasticity, or cognition (30, 43, 44). The enhanced plasticity and cognition that occurs because of HDAC2 deletion occludes the plasticity-enhancing abilities of VPA, indicating that HDAC2 is the major mediator of the effects of HDAC inhibition on cognitive function, at least in the hippocampus (30).

Fig. 1 The roles and regulation of HDAC2 in cognitive function.

HDAC2 inhibits the promoter acetylation (Ac) and expression of plasticity-associated genes. HDAC2 binding to chromatin is modulated by S-nitrosylation (S-n), which can be regulated by BDNF, nNOS, and NO under the control of synaptic plasticity–inducing stimuli such as calcium. The gene expression and protein stability of HDAC2 is further controlled by GR-mediated transcription and c-Abl–mediated phosphorylation, both of which are implicated in the increase of HDAC2 that is seen in AD.


Additional HDACs are shown to play more specific roles in certain types of memory. Focal deletion of Hdac3 from area CA1 of the hippocampus enhances object location memory in mice, mimicking the effects of the HDAC inhibitor NaB and the HDAC3-specific inhibitor RGFP136 (35, 36). Object recognition memory was not affected by Hda3 deletion or RGFP136 treatment, suggesting a specific role for HDAC3 in a subset of learning processes. Similarly, object recognition and location memory were unaffected by knockout of HDAC1 or HDAC2 (43).

Mice lacking the class II HDACs 4, 5, and 6 have also been examined for altered cognitive performance. Forebrain-specific deletion of Hdac4 resulted in a host of behavioral and plasticity defects, whereas no detectably altered behavior was reported in HDAC5 null mice (45). However, a second report did find learning defects in aged HDAC5 mice (46). On the other hand, mice lacking HDAC6 showed normal fear learning but enhanced spatial learning, indicating that class II HDACs can either promote or restrain cognitive function, depending on the context (47). Although the mechanisms of action of these HDACs in learning and memory remain to be determined, they likely act at least in part through nonhistone substrates because their expression is largely cytoplasmic and/or they show low deacetylase activity toward histone substrates (8, 9). The class II HDACs likely play little or no role in the cognitive-enhancing abilities of HDAC inhibitors, given that these compounds either preferentially or specifically target class I HDACs (10).

In addition to memory formation, processes such as memory reconsolidation and extinction also play important roles in normal cognitive function, and deficits in these processes are thought to contribute to anxiety and posttraumatic stress disorder (PTSD) (48). Although it appears not to have a major role in hippocampal synaptic plasticity or memory formation, HDAC1 does promote the extinction of recently formed (1-day-old) fear memories (49). The authors found that after extinction training, the expression of the activity-regulated gene cFos was decreased in parallel with H3 acetylation at the cFos promoter, whereas HDAC1 binding to the cFos promoter was increased. Hippocampal overexpression of HDAC1 facilitated (whereas knockdown inhibited) memory extinction in this paradigm (49).

More recent reports also implicate HDAC2 in fear memory extinction and have identified mechanisms that make “remote” (30-day-old) fear memories difficult to modify (31, 43). Gräff et al. (31) found that immediately after recall of 1-day-old memories, during what is considered the reconsolidation window, the abundance of cFos mRNA and cFos promoter acetylation was increased, whereas HDAC2 binding to the cFos promoter was reduced. These events appeared to be mediated, at least in part, by nNOS (neuronal nitric oxide synthase)–dependent nitrosylation of HDAC2 (described below and in Fig. 1). Thus, a complex interplay between multiple HDACs appears to occur during memory reconsolidation and extinction, differentially affecting the expression and promoter acetylation of cFos (and presumably other plasticity-related genes) during different phases of memory extinction.

In contrast to recent fear memories, “remote” (30-day-old) memories were resistant to extinction, and the aforementioned effects of memory recall on cFos expression, promoter acetylation, and HDAC2 binding were absent (31). However, treatment with the HDAC inhibitor CI-994 during remote memory recall facilitated acetylation and gene expression changes to mimic those that occur during recent memory recall. Accordingly, CI-994 treatment promoted structural and functional synaptic plasticity and enabled the extinction of remote fear memories (31). Likewise, HDAC2 knockout also accelerated the extinction of recent fear memories (43). Together, these findings indicate that HDAC2 acts to maintain memory fidelity, and that relief of HDAC2-mediated repression is required to make memories labile. It is worth noting that in many cases, mechanisms that act to stabilize long-term memory are desirable; it is only in specific circumstances, such as in PTSD, that these mechanisms would be considered pathological. The above findings suggest that HDAC inhibition could provide an effective treatment for PTSD and related disorders.

Information about the roles of the remaining HDACs in cognitive processes is sparse, and additional study is required to determine the roles of these enzymes in brain function. Nevertheless, a substantial and growing body of knowledge now exists about individual HDACs in a diverse array of cognitive processes. Together, these findings indicate a central role for HDAC2 in regulating structural and functional neuronal plasticity in various forms of learning and memory, as well as in mediating many of the positive effects of HDAC inhibition on cognition.

HDACs in Aging and Neurodegenerative Disease

A decline in cognitive performance is a normal consequence of aging (50). Although the molecular and cellular changes that occur in the brain with age remain poorly defined, it is clear that major alterations in gene expression are one defining feature of the aging process (50). It appears that the robust changes in gene expression normally associated with synaptic plasticity are also severely compromised in the aged brain. Peleg and colleagues (51) found that although more than 2000 transcripts showed altered expression 1 hour after fear conditioning in young (3-month-old) mice, just 16 transcripts were altered after the same treatment in aged (16-month-old) mice. This lack of transcriptional plasticity was associated with impaired learning ability as well as alterations in chromatin acetylation. Treatment of aged animals with HDAC inhibitors rescued the plasticity-induced gene expression and acetylation changes as well as learning ability (51, 52). Thus, HDAC inhibition has the potential to therapeutically ameliorate the cognitive decline that occurs with aging.

As with aging, neurodegenerative disorders, such as Alzheimer’s disease (AD), are characterized by sharp declines in cognitive function accompanying—and even preceding—neuronal death (10). Many studies have found decreased expression of plasticity-associated genes and reduced histone acetylation in various AD mouse models (29, 5356), although another study did not (57). HDAC2 abundance was increased in parallel with plasticity and acetylation changes in multiple AD mouse models and could be induced by amyloid β (Aβ) (Fig. 1) (55, 56, 58). Furthermore, examination of postmortem samples from AD patients revealed that HDAC2 abundance was substantially increased even at the earliest stages of AD pathology, suggesting that HDAC2 could be a driver of cognitive decline in this disease (55). Consistent with this hypothesis, HDAC inhibition in multiple AD mouse models rescued deficits in gene expression, acetylation, synaptic plasticity, and cognition (29, 33, 5356). Similarly, direct knockdown of HDAC2 in the CA1 of the hippocampus reverses defects in transcription, chromatin, synaptic plasticity, and learning in AD mice (55, 56). Thus, pathologically increased HDAC2 appears to be a key modulator of cognitive decline in AD mouse models, and likely also in humans.

In addition to affecting cognitive function in AD, HDACs also regulate genome stability and cellular toxicity in neurons (59, 60). HDAC1, which has limited roles in cognition, can either promote neuronal survival or have neurotoxic effects (6164). Inhibition of HDAC1 function is implicated in the pathology of both AD and amyotrophic lateral sclerosis (ALS) models (6163). However, despite the potential protective functions of HDAC1, HDAC inhibitors have shown efficacy in preventing neuronal toxicity in models of AD, ALS, Huntington’s disease, and other neurodegenerative diseases (60). Together, these findings indicate that HDACs, with HDAC2 prominent among them, play critical roles in the cognitive decline and neuronal death associated with aging and neurodegenerative disease.

HDACs in Neurodevelopmental and Mood Disorders

HDAC alterations may also be involved in neurodevelopmental and mood disorders. The transcript abundance of HDACs 1, 3, and 4 was increased in postmortem samples from schizophrenia patients (65). Consistently, postmortem samples also revealed hypoacetylation at the promoters of multiple schizophrenia-associated genes, whose expression was reduced in schizophrenia patients (66). In addition, deletions at the HDAC9 locus have been associated with schizophrenia, although the targets and mechanism of HDAC9 action remain unknown (67). Thus, although considerable further study will be required to understand the roles of histone acetylation in schizophrenia, deregulated HDAC activity may well contribute to disease pathology. Accordingly, attempts to treat schizophrenia patients and animal models with HDAC inhibitors have shown some promise but so far yield inconsistent results regarding their efficacy (12).

Like that of schizophrenia, the etiology of major depressive disorder may involve altered HDAC function. The abundance of HDAC2 was reduced in the nucleus accumbens (NAc) in both a “chronic stress” mouse model of depression and postmortem samples from depressed patients (68). Consistently, H3 acetylation was increased in the NAc, hippocampus, and amygdala in mice experiencing chronic or social defeat stress (68, 69). In contrast, another chronic stress paradigm increased HDAC2 abundance in the striatum of mice, indicating the brain region–specific effects of stress on Hdac2 expression (70). In parallel, HDAC2 binding to the promoter of Gdnf (encoding glial cell–derived neurotrophic factor) was increased in the striatum, whereas Gdnf promoter acetylation and gene expression were reduced. The antidepressant imipramine reverses each of the aforementioned alterations and rescues depression-related phenotypes in stressed mice. Short-term treatment with HDAC inhibitor, or expression of a dominant-negative HDAC2 construct in the striatum, also rescues depression-like phenotypes in stressed mice, functionally confirming the importance of the stress-induced increase in HDAC2. Consistent with the different effects of stress on Hdac2 expression and promoter acetylation in different brain regions, studies have often, but not always, found positive effects of HDAC inhibition on depression-like symptoms in mice (12, 6870).

Alterations in HDAC activity may also play a role in Rett syndrome (RTT), a neurological disorder with similarity to autism spectrum disorder (71). RTT is caused by mutations of MeCP2 (methyl CpG binding protein 2), a methyl-DNA binding protein and transcriptional repressor. Recent studies have shown that MeCP2 interacts with the NCoR (nuclear corepressor) complex, which includes HDAC3, and that a subset or RTT-causing mutations disrupts this interaction (72). Although the exact function(s) of the MeCP2/NCoR interaction is not currently known, it is likely that MeCP2 acts at least in part to coordinate local histone deacetylation with repressive DNA methylation. Mice bearing mutations in MeCP2 that block its binding to NCoR exhibit severe RTT-related phenotypes, supporting a critical role for this interaction. Activity-regulated phosphorylation of MeCP2 also inhibits the interaction with NCoR and HDAC3, suggesting one mechanism whereby neuronal activity could regulate lysine deacetylation (73). Further study will be required to fully define the transcriptional targets affected by this interaction, as well as to better understand the importance of these mechanisms in cognitive function. Histone deacetylation and HDACs are also functionally implicated in addiction and substance abuse; these findings have recently been reviewed elsewhere (74).

HDAC Target Genes

Although the complete set of transcriptional targets regulated by HDAC activity during neuroplasticity is not currently known, a number of studies indicate that HDAC activity in the nervous system preferentially affects genes encoding proteins involved in synaptic plasticity rather than globally affecting transcription. Consistent with this idea, the plasticity-enhancing effects of the HDAC inhibitor TSA were lost in mice that either lacked CREB or expressed a mutant form of CREB that cannot interact with CBP (27). These observations suggest that the acetylation of CREB target genes is required for the effects of HDAC inhibitors, and that HDAC activity likely regulates an overlapping set of genes. These effects could potentially also be due to changes in CREB protein acetylation (75).

A number of additional studies have examined the effects of HDAC inhibition on select, putative HDAC target genes. These studies have often focused on BDNF (encoding brain-derived neurotrophic factor), cFos, and other CREB-regulated transcripts, finding that expression and acetylation of such synaptic plasticity–related genes could be enhanced by HDAC inhibition (25, 51, 76). A recent study sequenced the RNA from hippocampal extracts after mice underwent fear memory extinction training when treated with either vehicle or the class I HDAC inhibitor CI-994 (31). This analysis identified 475 differentially expressed transcripts, many of which encoded proteins with synaptic plasticity–related functions.

Given the central role of HDAC2 in cognition and disease, a number of studies have focused specifically on genes regulated by HDAC2 (Fig. 1) (30, 55, 56). Guan and colleagues (30) found that HDAC2 bound to the promoters of a group of plasticity-associated genes that were not bound by HDAC1. In contrast, HDACs 1 and 2 bound equally to the regulatory regions of a number of housekeeping genes. Furthermore, in HDAC2 knockout mice, the acetylation of H3 and H4 within the promoters of these plasticity-associated genes was increased, as was the abundance of many of the corresponding proteins. Many of these same genes were regulated by HDAC2 in mouse models of AD (55, 56). In these mice, HDAC2 binding to the promoters of plasticity-associated genes was increased in parallel with decreased acetylation, decreased RNA polymerase II binding, and decreased gene expression. Reducing HDAC2 in these mice largely restored the deficits in promoter acetylation and gene expression, as well as restored cognitive function.

Collectively, these studies have identified a partial list of the transcripts regulated by HDAC activity in cognitive processes. These findings support the notion that HDAC inhibition can “prime” a specific group of genes, enriched for those that regulate neuronal function, to enhance their expression after a synaptic plasticity–inducing stimulus. These results are also consistent with the idea that HDAC-induced facilitation of gene expression largely uses the same signaling pathways, and affects the same target genes, that are normally engaged during synaptic plasticity. In this context, it is not surprising that HDAC inhibition can enhance synaptic plasticity and cognitive function in various systems.

Molecular Mechanisms of HDAC Signaling

Despite the critical roles that HDACs play in multiple cognitive processes, our understanding of the mechanisms linking HDAC activity to synaptic function is incomplete. Various HDACs are posttranslationally modified by multiple mechanisms, including phosphorylation, ubiquitination, acetylation, and nitrosylation (77). S-Nitrosylation of HDAC2 by nitric oxide (NO) appears to be particularly important in neurons (Fig. 1). In response to treatment with BDNF, NGF (nerve growth factor), or Ca2+ ionophore in rat cortical neurons, HDAC2 was rapidly nitrosylated on cysteines 262 and 274 in an nNOS- and NO-dependent manner (78). Nitrosylation did not affect the deacetylase activity of HDAC2 but rather inhibited its association with chromatin. Consistently, stimulation of PC12 cells with NGF, a plasticity-promoting neurotrophin, induced dissociation of HDAC2 from target gene promoters and enhanced histone acetylation at these same locations (78, 79). A non-nitrosylatable form of HDAC2 did not dissociate from target gene promoters upon NGF treatment and prevented the increase in acetylation at these sites normally induced by NGF. These findings indicate that nitrosylation can suppress the ability of HDAC2 to inhibit gene expression during cognitive function, and they also illustrate how HDAC residence at target gene promoters can antagonize histone acetylation activity.

Given the critical roles that BDNF and NO play in synaptic plasticity, it is tempting to speculate that these molecules constitute an important link between synaptic activity, chromatin modification, and activity-induced gene expression. Indeed, increases in HDAC2 nitrosylation were detected in cortical neurons within 5 min after BDNF treatment, consistent with a mechanism that could regulate activity-induced gene expression (78). The involvement of HDAC2 nitrosylation in memory formation has not formally been tested; however, increased nitrosylation was detected in hippocampal tissue 1 hour after fear conditioning (31). Furthermore, increased HDAC2 nitrosylation closely paralleled the enhanced acetylation and gene expression that occurs after memory recall. Indeed, preventing HDAC2 nitrosylation during the recall and extinction paradigm prevented the extinction of recent fear memories (31). Thus, it appears that HDAC2 nitrosylation is a key mediator of the chromatin-based changes in gene expression that occur during synaptic plasticity.

Because BDNF is a well-established HDAC2 target gene, it is worth noting that BDNF and HDAC2 could form the core of a positive feedback loop in synaptic plasticity (Fig. 1) (3). That is, the activity-dependent secretion of BDNF in response to a synaptic plasticity–inducing stimulus would be expected, through NOS and NO, to promote HDAC2 dissociation from chromatin. This removal of HDAC2 inhibition would then promote the expression of plasticity-related transcripts, including BDNF, which would further stimulate synaptic plasticity and further inhibit HDAC2-mediated repression. Similarly, stimuli that inhibit HDAC2 activity could prime BDNF expression, ultimately further inhibiting HDAC2 activity. Although this type of positive feedback loop has not been experimentally tested in neurons, it is an attractive mechanism to coordinate chromatin acetylation modifications with neuronal activity to enact lasting changes in the transcriptional potential of plasticity-associated genes.

An additional mechanism that can control HDAC2 activity in the brain is transcriptional regulation by glucocorticoid receptor (GR) signaling (Fig. 1). GR is a steroid receptor and transcriptional activator whose activity can be modulated by systemic or cellular stress (48). Activated GR (pGR) can bind to elements in the HDAC2 promoter and is thought to contribute to the increased abundance of HDAC2 seen in AD patients and mouse models (55). Treating hippocampal neurons with cellular stressors such as hydrogen peroxide or Aβ induces the activation of GR, binding of GR to the HDAC2 promoter, and HDAC2 expression. Intriguingly, GR activity can also be regulated by emotional stress (48), suggesting the possibility that GR-mediated up-regulation of HDAC2 could contribute to stress-induced cognitive dysfunction and depression.

A recent study found that phosphorylation can promote the stability of HDAC2, and this may contribute to AD pathology (58). Here, Gonzalez-Zuñiga et al. showed that HDAC2 could be phosphorylated by the tyrosine kinase c-Abl, inhibiting the polyubiquitination and proteasomal degradation of HDAC2 (Fig. 1). Activation of c-Abl, which could be induced by Aβ oligomers and is increased in the APP/PSEN1 (β-amyloid precursor protein/presenilin 1) AD mouse model, was paralleled by increases in HDAC2 protein abundance and chromatin binding. These effects could be reversed both in vitro and in vivo using a c-Abl inhibitor. It is likely that GR-mediated induction of HDAC2 transcription and c-Abl–mediated stabilization of HDAC2 protein work in concert to pathologically increase the abundance of this protein in AD. Thus, multiple mechanisms have now been described that can regulate HDAC2 activity in physiological or pathological contexts.


Research over the past 20 years has established lysine acetylation as an important mediator of synaptic plasticity and memory. Acetylation changes are modulated by neuronal activity and learning, and act to coordinate the expression of plasticity-associated genes. Although multiple HDACs participate in various forms of learning and memory, HDAC2 plays a central role in cognitive processes. Endogenous HDAC2 activity restrains structural and functional synaptic plasticity, inhibits multiple forms of learning and memory, and can be regulated by plasticity-inducing stimuli. It is also clear that HDAC2 abundance and activity can be regulated at both the transcriptional and posttranscriptional levels, the latter via nitrosylation and phosphorylation. Furthermore, dysregulation of HDAC2 and other HDACs contributes to the pathology of AD and other neurological disorders. In many of these cases, HDAC inhibitor treatment provides a promising therapeutic avenue to ameliorate the symptoms of such disorders. Continued research to better understand the roles of specific HDACs in various cognitive processes, the mechanisms that regulate them, and their modes of action promises to improve the efficacy and viability of HDAC inhibitors as therapeutic options.


Funding: Work in the Tsai laboratory is supported by funding from the NIH and the Human Frontier Science Program. Competing interests: The authors declare that they have no competing interests.
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