unique functional roles for class i and class ii histone deacetylases in central nervous system...

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ARTICLE IN PRESSG ModelN 1755 1–12

Int. J. Devl Neuroscience xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

International Journal of Developmental Neuroscience

j our na l ho me p age: www.elsev ier .com/ locate / i jdevneu

eview

nique functional roles for class I and class II histone deacetylases in centralervous system development and function

ichael J. Morris, Lisa M. Monteggia ∗

epartment of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA

r t i c l e i n f o

rticle history:eceived 1 September 2012eceived in revised form 11 January 2013ccepted 15 February 2013

a b s t r a c t

Non-specific pharmacological inhibition of the histone deacetylase (HDAC) family of enzymes has largelybeneficial effects in a variety of diverse contexts including cancer, cognitive function, and neurodegener-ation. This review will discuss the role of individual HDAC isoforms in brain function during developmentand in the adult. Importantly class I and class II HDACs exhibit distinct cellular and subcellular expres-

eywords:pigeneticDACynaptic functionearning

sion patterns and utilize different signaling pathways to influence their substrates. Moreover, dissociablephenotypic outcomes emerge following manipulation of individual HDACs in the brain. To date, pharma-cological inhibitors capable of targeting individual HDACs have proven difficult to develop, an obstaclethat must be overcome to unlock the substantial clinical promise of manipulating endogenous HDACisoforms in the central nervous system.

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TP © 2013 ISDN. Published by Elsevier Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Class I and class II HDACs have distinct cellular and subcellular expression patterns and influence cellular function through diversesignaling pathways. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. HDACs are critical for central nervous system development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. Class I and class II HDACs have distinct roles in learning and synaptic function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005. What are the upstream signaling pathways and downstream targets of class I and class II HDACs?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006. Broad potential clinical applications for isoform-specific HDAC inhibition in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Introduction

Histone deacetylases (HDACs) are an evolutionarily ancientnzyme family that regulate activity of their substrates by remov-ng acetyl groups from lysine residues (Gregoretti et al., 2004;ildmann et al., 2007). Histone deacetylases are so named based on

substrates (Kouzarides, 2000; Glozak et al., 2005; Ocker, 2010).

Alternatively, the histone acetyltransferases (HATs), by acetylation

of histone tails, neutralize their positive charge thereby relaxing

chromatin structure due to greater electrostatic repulsion from

negatively charged DNA, a modification associated with transcrip-

tional activation (Feng et al., 2007; Haberland et al., 2009a). In a

provocative recent study, Wang et al. (2009) found that both HATs

Please cite this article in press as: Morris, M.J., Monteggia, L.M., Uniqcentral nervous system development and function. Int. J. Dev. Neuros

heir ability to govern chromatin structural dynamics by deacety-ating N-terminal lysine residues within the protruding tails ofistone proteins, a modification associated with repression ofene transcription, however, the acetylation/deacetylation reac-ion occurs in at least 80 proteins and HDACs can act on many

∗ Corresponding author at: Department of Psychiatry, The University of Texasouthwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070,SA. Tel.: +1 214 648 5548; fax: +1 214 648 4947.

E-mail address: [email protected] (L.M. Monteggia).

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736-5748/$36.00 © 2013 ISDN. Published by Elsevier Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.ijdevneu.2013.02.005

and HDACs are found at transcribed regions of active genes, and

suggested that HDACs function to “reset” the conformational state

of chromatin by removing acetylation at active genes (Wang et al.,

2009).

Primarily through the use of non-specific, “pan-” HDAC

inhibitors which inhibit many or all HDACs, HDACs have been

ue functional roles for class I and class II histone deacetylases inci. (2013), http://dx.doi.org/10.1016/j.ijdevneu.2013.02.005

implicated in diverse biological processes, including but not 54

limited to, tissue specific developmental programming, apoptosis, 55

synaptogenesis, cognition, cancer, and neurodegenerative disease 56

(Bolger and Yao, 2005; Minucci and Pelicci, 2006; Hildmann et al., 57

dx.doi.org/10.1016/j.ijdevneu.2013.02.005


http://www.sciencedirect.com/science/journal/07365748

http://www.elsevier.com/locate/ijdevneu

mailto:[email protected]


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ARTICLEN 1755 1–12

M.J. Morris, L.M. Monteggia / Int. J

007; Barrett and Wood, 2008; Akhtar et al., 2009; Brunmeir et al.,009; Chuang et al., 2009; Haberland et al., 2009a). Biological func-ions of individual HDACs have been difficult to determine due tohe lack of specific pharmacological inhibitor compounds for par-icular HDACs. Moreover, constitutive knockout (KO) of many ofhe individual HDACs are lethal, underscoring the vital role of thesenzymes in normal development, but rendering the use of constitu-ive KO models unsuitable for study in the adult. Conditional KO andmall-interfering RNA (siRNA) strategies are now being employedo study the unique functional profiles of individual HDAC isoforms,ith the obvious benefit that the animals are viable and knockdown

an be made in a temporal- and anatomical region-specific manner.Attention has recently been lavished upon the HDACs due to

he efficacy of certain HDAC inhibitor compounds in treating someorms of cancer. To date two HDAC inhibitors have been approvedor cutaneous T-cell lymphoma (vorinostat and depsipeptide) andeveral are in phase II or III clinical trials for cervical and ovarianancer (Minucci and Pelicci, 2006; Duvic and Vu, 2007; Kristensent al., 2009). Beyond cancer, HDAC inhibitors are recognized forheir ability to influence a wide spectrum of neurodevelopmentalnd neurophysiological processes. For example, HDAC inhibitions neuroprotective in in vitro and in vivo models of neurotoxicitynd degeneration, and can improve cognitive function followingraumatic brain injury or neurodegeneration in animal modelsFerrante et al., 2003; Petri et al., 2006; Avila et al., 2007; Dompierret al., 2007; Fischer et al., 2007; Chuang et al., 2009; Dash et al.,009; Ricobaraza et al., 2009; Bardai and D‘Mello, 2011; Grafft al., 2012). Acute treatment with HDAC inhibitors enhances mem-ry formation in vertebrates and invertebrates and boosts cellularechanisms believed to underlie learning (e.g., long-term poten-

iation) (Levenson and Sweatt, 2006; Barrett and Wood, 2008;ederman et al., 2009; Graff and Tsai, 2011). Furthermore, there isvidence that drug addiction and affective disorder may be patholo-ies effectively targeted by HDAC manipulation (Renthal et al.,007; Tsankova et al., 2007; Malvaez et al., 2009; Morris et al., 2010;aniguchi et al., 2012). Clearly, the potential clinical applicationsf manipulating endogenous HDAC function transcend cancer andnclude neurodegenerative and psychiatric disorders.

The following review will discuss the diverse functional reper-oire of this important enzyme family highlighting the distinct rolesf class I versus class II HDACs in central nervous system develop-ent and adult brain function. The use of HDAC KO mice has begun

o reveal distinct and specific roles of individual HDACs in devel-pment as well as in disease. Therefore in many applications broadDAC inhibition will prove not as clinically beneficial as targeting

ndividual HDAC isoforms.

. Class I and class II HDACs have distinct cellular andubcellular expression patterns and influence cellularunction through diverse signaling pathways

Structural and functional differences as well as expression pat-erns provide a basis for grouping HDACs into at least 3 differentlasses in mammals (see Table 1 and Fig. 1). The class I HDACsHDAC1, 2, 3, and 8), are constitutively nuclear proteins, whereashe class II HDACs (HDAC4, 5, 6, 7, 9, and 10; class II HDACs can beurther divided into class IIa – HDAC4, 5,7, 9 or class IIb – HDAC6, 10)re expressed in a more cell-specific manner and shuttle betweenhe nucleus and cytoplasm (Fig. 1) (Chawla et al., 2003; Broide et al.,007; Haberland et al., 2009a). Class IV, currently consists of oneember, HDAC11, with little known of its function. The sirtuins,


ometimes referred to as the class III HDACs, possess deacetylasectivity but are functionally unrelated to HDACs and rely uponAD+ as opposed to zinc as a cofactor for enzymatic activity. Sir-

uins have been discussed in several recent reviews (Longo and

PRESSNeuroscience xxx (2013) xxx–xxx

Kennedy, 2006; Baur et al., 2012; Houtkooper et al., 2012) and will

therefore not be further considered here.

In the adult rat and mouse all 11 HDACs are expressed in

brain to some extent (Broide et al., 2007; Baltan et al., 2011).

Class I HDACs are relatively highly expressed, with the excep-

tion of HDAC8 which is expressed at low levels in most areas

of the brain. HDAC1 and 2 exhibit a unique spatial distribution

in developing chick and mouse brain suggesting divergent func-

tions of the two enzymes. As development progresses forebrain

expression of HDAC2 becomes relatively greater than hindbrain

expression, a pattern not seen for HDAC1 (Murko et al., 2010). Both

HDAC1 and 2 are expressed in neural progenitors, however, in the

3-month-old mouse brain HDAC1 is found predominantly in glia

and HDAC2 expression is expressed at low levels in glia but highly

and ubiquitously expressed in neurons (MacDonald and Roskams,

2008; Murko et al., 2010; Baltan et al., 2011). HDAC3 is exceptionalamongst class I HDACs in that it is found in cytoplasm and at theplasma membrane, as well as the nucleus in neurons throughoutthe brain (Takami and Nakayama, 2000; Longworth and Laimins,

2006). Two members of the class II HDACs, HDAC4 and 5, are highlyexpressed in brain (6, 7, 9, and 10 are expressed at lower levels)

with highest expression in basal ganglia, hippocampus, and cere-

bellum. HDAC6 is expressed in raphe serotonergic neurons in adult

mice, with weaker staining observed in hippocampus and other

brain regions (Fukada et al., 2012). Given the variable tissue- and

cell compartment-specific expression patterns for specific HDACs

in brain and other tissues it is expected that robust functional dif-

ferences exist between HDACs.

Generally speaking, although not without important exceptions,

class I HDACs are found in the nucleus, appear more impor-

tant for neuronal survival and proliferation, are expressed in all

tissues, and are capable of acetylating histones as well as non-

histone substrates. Alternatively, class II HDACs are expressed in

a more tissue-restricted manner, exhibit nucleocytoplasmic shutt-

ling, and thus are capable of influencing the acetylation status

of both histones and cytoplasmic, non-histone substrates (Fig. 1).

In contrast with most class I HDACs, class IIa show weak enzy-

matic activity by themselves, but through recruitment of class I

HDACs and interaction with the SMRT/NCoR co-repressor com-

plex carry out deacetylase function (Fischle et al., 2002). HDACs

lack intrinsic DNA-binding activity and must be recruited to tar-

get genes via their direct association with transcriptional activators

and repressors. In many cases the mechanisms by which individual

HDACs are attracted to and bind their specific target regions of the

genome or their cytoplasmic substrates are not well understood.

Furthermore, the bulk of experimental effort, and interpretation

of experimental results in studies of HDAC function, has focused

on the effects of HDACs on chromatin structure. These interpre-

tations may be misleading in the sense that HDAC interactions

with non-histone proteins are often ignored, both conceptually and

empirically. Acetylation of non-histones can increase or decrease

the DNA binding affinity of target proteins, increase or decrease

transcriptional activation and protein stability, as well as promote

or disrupt protein-protein interactions (Glozak et al., 2005; Ocker,

2010).

3. HDACs are critical for central nervous system

development

Constitutive KO has been a powerful tool for understanding the

functional relevance of individual HDACs in development. Consti-


tutive deletion of most HDACs is lethal, either during embryonic 180

development or very early postnatal with deleterious effects on 181

distinct tissues or cellular processes recognized as the proximal 182

cause of death (Haberland et al., 2009a). HCAC1 null mice exhibit 183


ARTICLE IN PRESSG ModelDN 1755 1–12

M.J. Morris, L.M. Monteggia / Int. J. Devl Neuroscience xxx (2013) xxx–xxx 3

Table 1Constitutive and conditional brain-specific knockout (KO) of individual histone deacetylase (HDAC) isoforms.Q4

Constitutive KO causeof death

Conditional brain KO-behavioral phenotype

Effect on neuronalviability

Reference(s)

Class IHDAC1(N) General growth defects Mild/no phenotype Toxic/protective Lagger et al. (2002); Morris et al. (2012); Kim et al. (2008);

Bardai et al. (2012)HDAC2(N) Cardiovascular defects Enhanced memory, LTP NRa Montgomery et al. (2007); Guan et al. (2009)HDAC3(N/C) Gastrulation defects Enhanced episodic

memoryToxic Montgomery et al. (2008); Bardai and D‘Mello (2011);

Bardai et al. (2012); McQuown et al. (2011)HDAC8(N) Viable, cranial defects NR NR Haberland et al. (2009a,b)

Class IIaHDAC4(N/C) Skeleton malformation Impaired learning, LTP Protective Vega et al. (2004); Akhtar et al. (2012); Sando et al. (2012);

Majdzadeh et al. (2008); Chen and Cepko (2009)HDAC5(N/C) Viable Enhanced cocaine

sensitivity; anhedoniaToxic Haberland et al. (2009a,b); Renthal et al. (2007), Linseman

et al. (2003)HDAC7(N/C) Endothelial cell defects NR Protective Chang et al. (2006); Ma and D‘Mello (2011)HDAC9(N/C) Viable NR NRb Haberland et al. (2009a,b); Morrison et al. (2006)

Class IIbHDAC6(C) Viable Hyperactive, anxiolytic Toxic/protective Hubbert et al. (2002); Fukada et al. (2012); Pandey et al.

(2007a,b); Dompierre et al. (2007); Rivieccio et al. (2009)HDAC10(N/C) NR NR NR Kao et al. (2002)

Class IVHDAC11(N/C) NR NR NR Gao et al. (2002)

In parentheses – subcellular localization; N = nucleus, C = cytoplasm; NR = not reported. LTP = long term potentiation.al ∼1

2on et

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a Brain-specific double KO of HDAC1 and 2 during embryonic development is leth009).b Truncated form of HDAC9, HDRP has shown neuroprotective properties (Morris

idespread growth defects and do not survive beyond embryonicay 10.5 (E10.5) (Lagger et al., 2002). Constitutive HDAC2 KOice die shortly after birth due to severe cardiovascular defects


Montgomery et al., 2007; Haberland et al., 2009a). Brain-specificeletion of both HDAC1 and 2 is also lethal before postnatal day 7Montgomery et al., 2009). The HDAC3 null mouse dies before E9.5ue to defects in gastrulation (Bhaskara et al., 2008; Montgomery

Leucinerich

HDAC1

HDAC2

HDAC3

HDAC8

HDAC4

HDAC5

HDAC7

HDAC9

HDAC6*HDAC10

Class I

Class IIa

Class IIb

Class IVHDAC11

ZnF

Protein domains

ig. 1. Comparison of classes I, II, and IV HDAC protein size and subcellular localizatioectangle). Class IIa enzymes are characterized by an N-terminal extension (solid black

ectangles represent serine phosphorylation sites. ZnF, zinc finger. *HDAC6 contains an id

week postnatal and leads to apoptosis/poorly developed brain (Montgomery et al.,

al., 2006).

et al., 2008). Constitutive HDAC8 KO mice survive but present with

abnormal cranio-facial development (Haberland et al., 2009b). Indi-

vidual constitutive KO of class II HDACs is similarly devastating,


however, HDAC5 and HDAC6 KO mice are exceptions and are viable, 194

although HDAC5 KOs have abnormal adult cardiovascular function 195

(Haberland et al., 2009a). Both HDAC5 and 9 are highly enriched 196

in muscle, brain, and heart, and mutation of HDAC9, as well as its 197

Subcellular Reference(s)localization

Amino acids

Nucleus

NucleusNucleus/

Nucleus/

Nucleus

Cytoplasm

482

Cytoplasm

488

428

377

Nucleus/CytoplasmNucleus/CytoplasmNucleus/Cytoplasm

1084

Cytoplasm

Cytoplasm

Nucleus

1122

912

1011

1215

669

347

Lagger et al. , 2002Haberland et al. , 2009

Gao et al. , 2002

Kao et al. , 2002

Grozinger et al. , 1999



Zhou et al. , 2001

Hu et al. , 2000

Kao et al. , 2000

Yang et al. , 1997Longworth & Laimins, 2001

Haberland et al. , 2009

n. All HDACs contain a highly conserved catalytic domain (represented by blackline) of approximately 600 residues not found in class I HDACs. Open circles andentical duplication of 2 catalytic domains.


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plice variant MEF2-interacting factor/histone deacetylase relatedrotein (MITR/HDRP) disrupts the appropriate developmental tim-

ng of myocyte differentiation (Mejat et al., 2005; Haberland et al.,009a). A double knockout of HDAC5 and HDAC9 is lethal dueo defective heart development (Chang et al., 2004). HDAC6 KO

ice have no discernible phenotype beyond hyperacetylated tubu-in (Hubbert et al., 2002; Zhang et al., 2003). Interestingly, HDAC6s alone amongst all HDACs in that its substrates are exclusivelyytoplasmic proteins. Whether this relates to its relatively limitedffect on gross phenotype is not clear. HDAC4 null mice die aroundostnatal week one due to skeleton malformation promoted byxcessive bone formation (Vega et al., 2004). The HDAC7 nullouse shows embryonic lethality due to blood vessel rupture and

loss of the integrity of endothelial cell junctions, which is con-istent with the high expression of HDAC7 in endothelial cellsChang et al., 2006). These observations highlight the fundamen-al necessity of HDAC function for normal development as wells the fact that there is some degree of functional redundancyetween HDACs, at least during embryonic and early postnatalevelopment.

Early observations using pan-HDAC inhibitor compoundsemonstrated the importance of HDAC function for tissue-specificmbryonic and neonatal development. Pan-HDAC inhibitors pro-ote the differentiation of embryonic stem cells, and intriguingly,

re able to potentiate somatic cell reprogramming to pluripotencyLee et al., 2004; Siebzehnrubl et al., 2007; Brunmeir et al., 2009;retsovali et al., 2012). In brain, broad HDAC inhibition inducesifferentiation of embryonic cortical neuronal progenitor cells toeurons, and promotes survival of neural progenitors in the hip-ocampus (Hsieh et al., 2004; Siebzehnrubl et al., 2007; Shakedt al., 2008; Kim et al., 2009). Inhibition using the HDAC1- andDAC3-preferring compound MS-275 increases differentiation ofeural precursor cells from the subventricular zone, decreases theumber of oligodendrocytes, and increases the number of neu-ons (Siebzehnrubl et al., 2007). Collectively, results using HDACnhibitors demonstrate that blockade of normal HDAC function atertain time periods during embryonic development shift the fatef neuronal progenitors from glial to neuronal and strongly impli-ate deacetylase enzymes in cell-fate decisions in the developingrain.

Both class I and class II HDACs are involved in the proper devel-pment of specific tissues, however, class I appear to be moreelevant for brain development. Montgomery et al. (2009) usedhe Cre-lox system under the control of the GFAP promoter toelete HDAC1, HDAC2 or both HDAC1 and 2 concurrently (HDAC1/2KO) in the brain beginning at E13.5 (Montgomery et al., 2009).hey discovered that HDAC1/2 DKO severely disrupted cortical,ippocampal, and cerebellar organization, and the mice did not sur-ive beyond postnatal day 7. Neuronal precursors in HDAC1/2 DKOice failed to differentiate into neurons, and instead underwent

poptosis. By contrast mice with single deletions of HDAC1 or 2ere viable and exhibited no detectable developmental phenotype,emonstrating that HDAC1 and 2 have redundant functions duringeural development. HDAC1 and HDAC2 also play redundant roles

n the regulation of oligodendrocyte development by repressinghe Wnt/�-catenin pathway, suggesting that glial as well as neu-onal differentiation require HDACs (Ye et al., 2009). Previous workas also suggested redundancy of HDAC1 and 2 function for car-iac development (Montgomery et al., 2007). However, dissociableoles for HDAC1 and 2 on cell proliferation have been documented.or example, HDAC1 is essential for embryonic stem cell prolif-ration by repressing the expression of cell cycle inhibitors (e.g.,


yclin associated kinases), and although HDAC2 and 3 are upregu-ated in embryonic stem cells with HDAC1 KO, these class I HDACsre unable to compensate for the loss of HDAC1 function (Laggert al., 2002).


As suggested by the distinct neurodevelopmental expression

patterns of HDAC1 and 2 described above, it is likely that at

some point in early postnatal development the functional prop-

erties of HDAC1 and 2 undergo a switch, after which the roles of

these enzymes in the adult brain are established. Our laboratory

recently reported that HDAC1 and 2 function as a developmen-

tal “switch” that governs excitatory synapse maturation early in

development (Akhtar et al., 2009). While broad HDAC inhibition

using trichostatin A (TSA) decreases spontaneous miniature excit-

atory post-synaptic currents (mEPSCs) in hippocampal cell culture,

knockdown of HDAC1 or HDAC2 has specific effects that depend on

the maturational state of neurons (Nelson et al., 2006; Akhtar et al.,

2009). HDAC1/2 knockdown during early synaptic development,

day 5 in vitro (5 DIV) increased mEPSC and synaptic vesicle mobi-

lization, however, single KOs yielded no phenotype. Surprisingly,

single-cell recordings made from HDAC1 or 2 deficient neurons at16 DIV, a time point in which synapses in cultured hippocampalneurons share all of the functional and structural characteris-tics of mature synapses formed in vivo (Kavalali et al., 1999)

showed that knockdown of HDAC2 reduced mEPSC frequency,while HDAC1 knockdown was without effect, thus unmasking an

important developmental interaction between HDAC1 and 2 and

synaptic function. Furthermore, over-expression of HDAC2 pro-

duced the opposite phenotype – an increase in mEPSC frequency in

mature neurons, similar to what is observed following knockdown

of both HDAC1 and 2 in immature neurons. Miniature inhibitory

post-synaptic currents (mIPSCs) displayed normal frequency and

amplitude in HDAC1/2, HDAC1, and HDAC2 knockdown cultures.

These results indicate that HDAC1 and 2 promote synaptic network

stability during early time points in development by specifically

repressing excitatory synapse maturation, and that HDAC1 and 2

have functionally redundant effects on synaptic transmission in

immature neurons although they become functionally divergent

as neurons mature.

We have recently found that HDAC4 or HDAC5 knockdown in

hippocampal cell cultures had no impact on synaptic transmission

in hippocampal neuronal cultures (Kim et al., 2012). Therefore,

class I and class II HDAC knockdown have dissociable effects on

basal synaptic function as assessed in hippocampal neurons. Any

roles in synaptic transmission for the class I HDAC, HDAC3, or

the class II HDACs, HDAC6 and HDAC9, which are all expressed in

brain, have not yet been elucidated. These studies will be impor-

tant in order to clearly establish whether there are dissociable roles

for class I versus class II HDACs in regulating synapse function.

HDAC9 has been implicated in neuronal maturation. As cortical

cells mature, HDAC9 is increasingly transported from the nucleus to

the cytoplasm. This relocation is functionally relevant as an HDAC9

mutation that causes nuclear retention leads to defective cellular

maturation and inappropriate expression of genes that are impor-

tant for dendritic growth. Movement to the cytoplasm is regulated

by neural activity, and impacts expression of the immediate early

gene c-fos (Sugo et al., 2010).

4. Class I and class II HDACs have distinct roles in learning

and synaptic function

Chromatin dynamics are sensitive to experimental manipu-

lations that foster associative learning and long-term memory

formation. Specific histone modifications, including acetylation

and methylation, likely influence memory formation by modify-

ing promoters of transcription factors, neurotransmitter receptors,


cytoskeletal proteins, and other cellular substrates (Barrett and 323

Wood, 2008; Morris et al., 2010). Several laboratories have 324

demonstrated that pharmacological inhibition of HDACs improves 325

cognitive function in various learning and memory paradigms. 326


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ntrahippocampal or systemic treatment with HDAC inhibitorsnhances the acquisition and extinction of conditioned fearesponses (Yeh et al., 2004; Lattal et al., 2007; Bredy and Barad,008). Similarly, in a less aversive episodic memory task, the novelbject recognition task, treatment with the HDAC inhibitor sodiumutyrate in wild-type mice enhances memory, and does so in a

ong-term fashion as sodium butyrate-treated animals continuedo show evidence of memory long after untreated mice (Stefankot al., 2009).

Recent observations strongly suggest that class I HDACs (par-icularly HDAC2), but not class II HDACs, act as an endogenousestraint on memory formation. Mice with neuron-specific over-xpression of HDAC2 using the tau locus perform poorly in theorris water maze spatial task and in a fear conditioning paradigm,

elative to wild-type mice (Guan et al., 2009). HDAC1 over-xpression, however, had no effect on fear conditioning or wateraze learning. In addition, a brain-wide embryonic KO of HDAC2

urprisingly and robustly improved cognitive function in mice.n spite of 82% sequence homology between HDAC1 and HDAC2Brunmeir et al., 2009), and a demonstrated redundancy of func-ion in embryonic brain (Montgomery et al., 2009), the effects of

anipulating the two enzymes are clearly dissociable as regardsemory formation in adults.The above results strongly suggest that HDAC2 is important for

he memory-boosting effects of broad HDAC inhibition in the brain,owever, post-training delivery of the class I-specific inhibitorS-275, which preferentially inhibits HDAC1 and HDAC3 activity,

nto the hippocampus enhanced learning in an episodic memoryask (Hawk et al., 2011). Further evidence for an impact of spe-ific manipulation of HDAC1 on memory was recently providedy Bahari-Javan et al., however, they found an enhancement ofear extinction learning when HDAC1 was over-expressed specif-cally in the hippocampus, and a decelerated rate of extinctionn mice with inhibition of HDAC1 in hippocampus (Bahari-Javant al., 2012). These data contradict previous work with pan-HDACnhibitors and suggest that HDAC1 in hippocampus is required forormal extinction of fear responses. Moreover, HDAC1 manipu-

ation had no effect on episodic or working memory. Althoughhese results are not necessarily consistent with previous reportsegarding extinction learning, they suggest the exciting possibilityhat individual HDACs are involved in different forms (e.g., associa-ive versus episodic memory) or stages of memory formation (e.g.,cquisition and extinction).

Another class I HDAC, HDAC3, may similarly act as a restraint onearning and memory potential. A focal deletion of HDAC3 in theA1 region of the hippocampus enhanced long-term episodic mem-ry for an object that had been displaced from a previously learnedocation, however, had no effect on memory for the object itselfi.e., novel object recognition) consistent with the known impor-ance for hippocampal function in spatial memory (McQuown et al.,011). It will be important to determine if brain-wide HDAC3O yields a similar phenotype as HDAC2 KO in other behavioral

asks. This would be surprising as HDAC3 differs from HDAC2n terms of subcellular expression patterns and protein–proteinnteractions. A KO of HDAC3 in the hippocampus increases thexpression of HDAC4, which may complicate the interpretation ofhe effect of HDAC3 inhibition on memory formation (McQuownt al., 2011). Our laboratory has recently reported that a postna-al forebrain KO of HDAC4, but not HDAC5, forebrain KO, impairsearning and memory in mice (Kim et al., 2012). Furthermore, aecent study found that a truncated form of HDAC4 led to learningnd memory and neurotransmission deficits by repressing genes


mportant for synaptic plasticity and synapse structure (Sandot al., 2012). Thus, the impact of HDAC3 inhibition could be dueo a subsequent increase in HDAC4 expression. Taken togetherhe data establish that manipulation of class I or class II HDACs

PRESSNeuroscience xxx (2013) xxx–xxx 5

can have opposing effects on adult learning behavior and memory

formation.

Consistent with the results from behavioral studies demonstrat-

ing improved memory with HDAC inhibition, and perhaps pointing

to a mechanistic cellular underpinning for the behavioral pheno-

types that emerge following HDAC inhibition, are findings showing

that HDAC inhibitors enhance long-term potentiation (LTP) at hip-

pocampal synapses and also in the amygdala, two brain regions

that are essential for associative learning (Levenson et al., 2004;

Yeh et al., 2004; Vecsey et al., 2007; Barrett and Wood, 2008).

LTP, an activity-dependent increase in synaptic strength, is widely

regarded as an electrophysiological correlate of learning (Bliss

and Collingridge, 1993; Kim and Linden, 2007). Perfusion of hip-

pocampal slices with HDAC inhibitors sodium butyrate and TSA

enhance LTP at the Schaffer-CA1 synapse (Levenson et al., 2004).

Furthermore, using weak LTP-induction parameters (i.e., a singletrain of 100 Hz stimulation), HDAC inhibitor treatment transformsearly-phase LTP, which is protein synthesis-independent, into sus-tained and robust late-phase LTP, which requires protein synthesis

(Vecsey et al., 2007). As with performance in learning in mem-ory tasks, HDAC2 appears to be the most relevant enzyme as

over-expression of HDAC2 impairs, while KO enhances, LTP in

the hippocampal CA1 subregion (Guan et al., 2009). HDAC1 over-

expression, on the other hand, had no impact on LTP, and our

laboratory has recently found that forebrain-specific KO of HDAC1

also does not affect LTP in the CA1 (Morris et al., 2012). Interest-

ingly, a forebrain, neuron-specific postnatal KO of HDAC4 produces

deficits in hippocampal CA1 LTP, while HDAC5 is without effect

(Kim et al., 2012). This is consistent with the impact of HDAC4

or 5 KO on learning and memory performance in mice discussed

above, and demonstrates a double dissociation between the effects

of manipulating class I as opposed to class II HDACs on synaptic

plasticity as well as learning.

The class I HDACs, HDAC2 and HDAC3 have been dubbed an

“endogenous negative regulator of memory formation” or “a molec-

ular brake pad” for long-term memory formation (Guan et al., 2009;

McQuown and Wood, 2011), respectively. There are few precedent

studies reporting global learning and memory enhancements fol-

lowing deletion of a gene and the consistent observation that HDAC

inhibition or KO benefits cognitive function as well as enhances

plastic events at synapses that likely support learning and memory

is an exciting development in the study of the molecular neuro-

biology of memory. From the evolutionary biologist’s perspective,

there must be a physiological benefit to the presence of enzymes

that restrain the learning potential of an organism. HDAC1 or 2

are clearly necessary during embryonic brain development but

appear to be superfluous in adult brain given that mice that lack

either enzyme are viable, and indeed thrive. One general func-

tion of the class I HDACs may be to maintain a “homeostatic”

level of gene activation, potentially in a developmental-stage spe-

cific fashion, thus acting as a check on the deleterious effects of

unfettered transcription at critical periods during development or

possibly in adult brain as well. Unchecked transcription of HDACs

gene targets could manifest as enhanced plasticity, as suggested

by recent data (Akhtar et al., 2009; Guan et al., 2009). Although

it seems unlikely, one possibility is that continued expression in

adult brain of some members of the class I HDACs is essentially

vestigial. In other words continued expression in adult brain, from

an evolutionary fitness perspective, is inconsequential. It is per-

haps laboratory sleight of hand to uncover a memory-boosting

effect of inhibiting molecules in the adult brain that are essential

for normal embryonic and neonatal development. More likely is


that we are yet to discover the necessity of HDAC1 and HDAC2 for 455

adult brain function. One recent study suggests that HDAC2 in par- 456

ticular is required for adult, but not embryonic, neurogenesis in 457

the hippocampal dentate gyrus, although the functional relevance 458


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f hippocampal neurogenesis itself is not completely understoodJawerka et al., 2010).

. What are the upstream signaling pathways andownstream targets of class I and class II HDACs?

Clear distinctions can be drawn between class I and class IIDACs regarding the upstream signaling pathways that influence

heir activity, as well as the protein complexes in which class I orlass II HDACs associate. This may be in part due to the differencesn basal subcellular localization of the two classes of HDACs. Fur-hermore, class I and class II HDACs exhibit differential affinity andctivity at acetylated substrates. While class I HDACs possess potenteacetylase activity (HDAC3 is an exception), class II HDACs arenzymatically inactive alone. Deacetylase activity of class IIa HDACss likely due to association with other class I HDACs, particularlyhe SMRT/NCoR/HDAC3 complex, as class IIa HDACs preferentiallynteract with HDAC3 over HDAC1 or 2 (Huang et al., 2000; Fischlet al., 2002; Lahm et al., 2007).

Calcium-calmodulin kinases (CaMK) are bona fide upstreamediators of class IIa HDAC activity. CAMKI and II phosphory-

ate and induce nuclear export of HDAC4 and 5, although a kinasether than CaMK may be responsible for phosphorylating HDAC4McKinsey et al., 2000; Zhao et al., 2001). CaMKI and CaMKIV areapable of phosphorylating all four class II HDACs (Zhao et al., 2001;arra and Verdin, 2010). Protein kinase D1 may also act as an impor-ant class II kinase, however, thus far this has only been establishedn vascular smooth muscle cells, not yet in neurons (Xu et al., 2007).hosphorylation of the N-terminus and association with 14-3-3roteins leads to a conformational change that exposes a nuclearxport signal, therefore the net balance between the phosphory-ated and unphosphorylated state of class IIa HDACs determinesubcellular localization, and downstream effects on transcriptionf class IIa HDAC targets (Verdin et al., 2003; Yang and Gregoire,005). The cyclic-AMP (cAMP) pathway may also be an importantignaling cascade for the regulation of class II HDACs, as a recenttudy by Taniguchi et al. (2012) suggests. cAMP induces transportf HDAC5 to the nucleus which is associated with dephosphoryla-ion of HDAC5 at serine 279 (s279), a modification that is mediatedy increased protein phosphatase 2A activity and important forehavioral responses to acute cocaine treatment.

Little is known about the upstream signaling cascades thatffect class I HDAC activity. Similar to class II HDACs, phosphory-ation enhances class I enzyme activity and promotes co-repressoromplex interactions (Cai et al., 2001; Pflum et al., 2001; Smilliet al., 2004; Sun et al., 2007). HDAC1 and HDAC2 form severalo-repressor complexes, which are distinct from those formed byDAC3. Co-repressor complexes formed with Sin3, MECP2, NuRD,oREST, and NODE are responsible for delivering HDACs 1 and 2o their intra-nuclear targets, whereas HDAC3 associates with theMRT/NCoR complex (Jones et al., 1998; Guenther et al., 2001; Yout al., 2001; Brunmeir et al., 2009). Nitric oxide (NO) is a recentlyiscovered upstream regulator of HDAC2 activity as it dissocia-es HDAC2 from CREB-regulated gene promoters, which leads toncreased transcription of c-fos, VGF, nNos, and erg-1 (Nott et al.,008; Nott and Riccio, 2009). NO-dependent modulation of HDAC2

s needed for dendritic growth in vitro (Nott et al., 2008; Nott andiccio, 2009).

Less than 10% of all genes are regulated by HDACs, and HDACnhibition leads to gene repression as well as activation depend-ng on the specific gene target (Glaser et al., 2003; Kato et al.,


004; Nusinzon and Horvath, 2005; Peart et al., 2005). The ratiof up to downregulated genes appears to be approximately equal,trongly suggesting that HDACs are not global transcriptionalepressors (Nusinzon and Horvath, 2005; Minucci and Pelicci,


2006). Upregulation of specific genes following HDAC inhibition,

however, does not rule out secondary effects that may result in

transcriptional repression (e.g., disinhibition of a repressor).

The N-terminal domain of class II HDACs interacts with tissue-

specific transcription factors and co-repressors. This has been

convincingly demonstrated for the interaction between class II

HDACs and myocyte enhancer factor-2 (MEF2), a transcription fac-

tor that is critical for neuronal survival and apoptosis in response

to extracellular signals, along with well known roles in regulat-

ing genes critical for muscle differentiation (Chawla et al., 2003;

Shalizi and Bonni, 2005). A MEF2 binding site on the N-terminal

domain of class II HDACs promotes their nuclear localization until

the necessary cellular signal (e.g., CaMKs) releases class II HDACs

from MEF2 (Lu et al., 2000; Gregoire and Yang, 2005; Shalizi and

Bonni, 2005). Phosphorylation of conserved class IIa HDAC ser-

ine and threonine residues in the N-terminus interfere with theMEF2-HDAC association and unmask HDAC binding sites for 14-3-3 proteins which lead to nuclear export. This interaction betweenMEF2 and class IIa HDACs is established in developing muscle, and

it appears to be relevant for brain function as well (Chawla et al.,2003; Shalizi and Bonni, 2005; Parra and Verdin, 2010). Nuclear

import of HDAC5 in neurons results in reduced MEF2-dependent

transcription in neurons, and subsequently an increase in apoptosis

of depolarized neurons (Linseman et al., 2003). Along with binding

to, and interfering with the transcriptional activation domain of

MEF2, all four class IIa HDAC isoforms potentiate the sumoylation

of MEF2 in HEK293, and HeLa cells, a modification that represses

transcription (Gregoire and Yang, 2005).

There are different thresholds of activity for shuttling HDAC4

or 5 out of the nucleus. Spontaneous activity is sufficient to drive

HDAC4 out of the nucleus, however, HDAC5 remains and requires

calcium influx through L-type calcium channels or the NMDA

receptor (Chawla et al., 2003). In myocytes calcium influx and elec-

trical activity increase the expression of the HDAC9 splice variant

MITR/HDRP, which lack a deacetylase domain (Mejat et al., 2005).

As with other class IIa HDACs, MITR/HDRP is thought to repress

the expression of myogenic genes by inhibiting MEF2-dependent

transcriptional events (Mejat et al., 2005). An exciting possibility is

that the level of recent activity in a synaptic circuit can differentially

“tag” distinct HDAC isoforms which subsequently relieve repres-

sion of specific genes regulated by, for example, HDAC5. Elucidating

the activity-dependent molecular pathways that trigger chromatin

modifying enzymes will substantially advance our understanding

of the contribution of HDAC isoforms to brain development, synap-

tic function, and complex behavior.

Class I HDACs regulate the expression of subsets of genes

involved in mediating plastic cellular events (e.g., synapse devel-

opment, activity-dependent changes in synaptic strength, and

cardiovascular hypertrophy) during development and adulthood.

HDAC2 binds to several synaptic plasticity-related genes – BDNF,

Erg1, Creb1, CBP, nrn1, NMDA receptor subunit genes, and fos,

as well as genes important for synapse formation (Guan et al.,

2009). The fact that HDAC2 binds at CREB and CBP gene promoters

suggests that HDAC2 may communicate with a well-established

CREB–CBP pathway to regulate activity-dependent gene expression

and memory formation (Guan et al., 2009). Interestingly, CREB is

required for the enhancement of LTP in hippocampal slices follow-

ing non-specific HDAC inhibition (Vecsey et al., 2007). Additionally,

the coREST complex, an important regulator of neuron-specific

genes, for example genes encoding ion channels, synaptic vesicle

proteins, and neurotransmitter receptors, preferentially associates

with HDAC2 relative to HDAC1 (Schoenherr and Anderson, 1995).


Following treatment with the HDAC inhibitor MS-275, which pref- 584

erentially inhibits HDAC1 and to a lesser extent HDAC3, Covington 585

et al. (2009) found upregulation of various genes involved in den- 586

dritic remodeling (e.g., SLIT, TGF˛, JNK, and Rho) as well as various 587


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ranscription factors that have been implicated in memory forma-ion (e.g., CREB, REST, coREST, STAT, and nrn1).

Candidate genes for mediating learning and memory enhance-ents that result from HDAC inhibition include Nr4a1 and Nr4a2hich code for the immediate early transcription factors Nurr77

nd Nurr1, respectively. These genes have previously been impli-ated in memory, affective behavior, and addiction and increasedxpression of Nr4a1 and Nr4a2 mRNA is observed 2 h after trainingn fear conditioning (von Hertzen and Giese, 2005; Colon-Cesariot al., 2006; Rojas et al., 2007; Vecsey et al., 2007). Treatment withSA immediately after contextual fear conditioning increased thecetylation of H3 and H4 at the promoters of Nr4a1 and Nr4a2 andnhanced the expression of Nr4a1 and Nr4a2 mRNA relative toild type and CREB mutant mice, an effect not observed follow-

ng TSA treatment without prior fear conditioning training (Vecseyt al., 2007). Additionally, TSA treatment leads to recruitment ofNA polymerase and transcription factor IIB to the Nr4a1 promoter

n vitro (Fass et al., 2003). The memory enhancing effects of HDAC3eletion require the HAT CREB binding protein (CBP), and subse-uent expression of Nr4a2, a CREB dependent gene, as CBP mutantso not exhibit enhanced LTP following HDAC inhibition and siRNAor Nr4a2 prevents the improved memory effect (McQuown and

ood, 2011). It is not known if HDAC1 or 2 manipulation impactsr4a1 or Nr4a2 expression, and this could be a molecular pathway

hat specifically mediates HDAC3 involvement in certain forms ofearning.

A better understanding of the protein complexes in whichDACs associate, along with the cross talk between epigeneticathways, will be critical for mechanistically determining howDACs influence gene expression, and ultimately synaptic functionnd behavior. For example HDAC1 and 2 are known to form partf a multiprotein corepressor complex with methyl-CpG bindingrotein 2 (MeCP2), a protein that binds to methylated CpG din-cleotides (Jones et al., 1998; Dannenberg et al., 2005; Monteggiand Kavalali, 2009). Although the functional relevance of this inter-ction is not yet known, interruptions to the normal arrangementf this complex are likely be clinically relevant as the neurode-elopmental disorder Rett syndrome is caused by mutations inECP2 (Amir et al., 1999). The MeCP2–HDAC1/2 complex may be

mportant for stabilizing heterochromatin and TSA treatment canelieve transcriptional repression by MeCP2 (Jones et al., 1998; Nant al., 1998). HDACs also interact with the DNA methyltransferaseDNMT) enzymes responsible for adding methyl groups to specificytosine nucleotides of DNA, which is an important mechanism forene silencing. DNMT1, necessary for maintenance methylation ofNA, recruits HDAC1 and 2 as well as the histone methyltrans-

erase Suv39h1 (Espada et al., 2004). HDAC1 and 2 have also beenhown to interact with DNMT3a and DNMT3b, both de novo DNMTsFuks et al., 2000, 2001; Bai et al., 2005). An example of a functionalutcome of DNMT-HDAC interaction has been demonstrated foreurite outgrowth. DNMT3b activity is important for neurite out-rowth, and this is mediated by DNMT3b interaction with HDAC2Bai et al., 2005).

. Broad potential clinical applications for isoform-specificDAC inhibition in the brain

Beneficial effects of HDAC inhibition have been demonstratedsing in vitro as well as in vivo models of neurodegenerative dis-ase. Importantly, broad HDAC inhibition is neuroprotective whenells are challenged by diverse insults including polyglutamine tox-


city, cuprizone, glutamate, and ischemia (Ferrante et al., 2003;ockly et al., 2003; Jeong et al., 2003; Ryu et al., 2003; Faracot al., 2006; Leng and Chuang, 2006; Rivieccio et al., 2009). How-ver, contradictory evidence is available demonstrating that HDAC


inhibition can induce apoptosis in cerebellar granule neuron cul-

tures and cortical neurons undergo apoptosis following chronic

HDAC inhibition (Salminen et al., 1998; Boutillier et al., 2003;

Langley et al., 2008) One potential reason for the conflicting results

with pan-HDAC inhibitors may be that distinct HDAC isoforms

are pro-apoptotic or neuroprotective (Table 1). Separate studies

have documented the pro-apoptotic potential of HDAC1, HDAC3,

and HDAC5 in contrast to neuroprotection afforded by HDAC4,

HDAC6, HDAC7, and the alternatively spliced form of HDAC9, HDRP

(Linseman et al., 2003; Bolger and Yao, 2005; Kim et al., 2010; Bardai

and D‘Mello, 2011). Thus, the impact of HDACs on neuronal viability

is isoform-specific, and not related to class (i.e., class I vs. class II).

Overexpression of the class I HDAC and HDAC3 is highly toxic

to neurons, likely through a cooperative interaction with another

class I HDAC, HDAC1. Indeed inhibition of HDAC1 ameliorates cell

death induced by HDAC3, and vice versa. While HDAC1 knockdownhas previously been shown to enhance apoptosis in cultured cor-tical neurons (Kim et al., 2008), recent data suggest a mechanismwhereby HDAC1 behaves as a “molecular switch” between neu-

roprotection and neuronal apoptosis. The neurotoxic properties ofboth HDAC1 and HDAC3 are prevented by inhibition of the GSK3�,

a kinase implicated in a number of neurodegenerative diseases,

or by activation of the IGF-1-Akt pathway, which inhibits GSK3�,

a likely upstream effector of HDAC3. On the other hand HDAC1

is neuroprotective as a result of interactions with HDRP, a trun-

cated form of HDAC9 previously established as neuroprotective

(Morrison et al., 2006; Bardai et al., 2012). HDRP interferes with the

death-promoting HDAC1–HDAC3 interaction is capable of recruit-

ing HDAC1 to the c-Jun promoter, deacetylation of which favors

neuronal viability. Thus, an individual HDAC isoform can be both

neurotoxic and neuroprotective depending upon cellular context

and protein–protein interactions with distinct binding partners.

HDAC1 appears to be a central player in establishing cell viability by

partnering with HDAC3 to promote apoptosis, or with HDRP con-

vey neuroprotection. Interestingly, and an exception to the strict

nuclear localization of HDAC1, in humans with multiple sclerosis

or in demyelination models in animals, HDAC1 is observed in axons.

The axonal localization appears to be mediated by calcium and

axonal HDAC1 is capable of binding to alpha-tubulin and the motor

protein kinesin to inhibit mitochondrial transport, an effect that is

independent of HDAC6 activity. Inhibition of HDAC1 following glu-

tamate toxicity or TNF-alpha treatment reverses the mitochondrial

transport deficit (Kim et al., 2010).

The class II HDAC, HDAC4 has also been shown to promote

neuroprotection and headway is being made in determining the

molecular pathways responsible (Majdzadeh et al., 2008; Chen

and Cepko, 2009; Hageman et al., 2010). In cultured cerebellar

granule neurons, overexpression of HDAC4 protects from low-

potassium induced apoptosis, and this may require inhibition of

cyclin-dependent kinase-1 as well as prevention of maladaptive

cell-cycle progression (Majdzadeh et al., 2008). HDAC4 may be

necessary for the survival of retinal neurons, as in vivo siRNA

against HDAC4 in the developing mouse retina promoted apopto-

sis, and HDAC4 overexpression led to a significantly greater number

of bipolar cells (Chen and Cepko, 2009). Moreover, in a mouse

model of retinal degeneration, HDAC4 overexpression enhanced

photoreceptor survival, an effect blocked by expression of a dom-

inant negative form of the HIF1�, a protein important for oxygen

homeostasis (Chen and Cepko, 2009). Data implicating other class

IIa HDACs in apoptotic pathways or neuroprotection are sparse,

however in cerebellar granule neurons overexpression of HDAC5

led to enhanced cell death in neurons depolarized with potas-


sium chloride (Linseman et al., 2003). By contrast HDAC7 appears 713

neuroprotective for cerebellar granule neurons challenged by low 714

potassium culture media by repressing c-Jun expression (Ma and 715

D‘Mello, 2011). 716


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The class IIb HDAC, HDAC6 is an attractive target for cellu-ar protection in the context of neurodegenerative disease (Dund Jiao, 2011). HDAC6, which is critical for the clearance of mis-olded cytoplasmic proteins, is increased in cortical neurons inlzheimer’s patients, which is consistent with reduced acetylationf tubulin in cortical neurons in these patients (Hempen and Brion,996; Ding et al., 2008). The affinity of HDAC6 for cytoskeletallements, and its regulation of cytoskeletal dynamics, may play aole in impaired trafficking in neurological disorders. In an animalodel of Huntington’s disease inhibition of HDAC6 reversed the

bserved transport deficits, in part by increasing vesicular traffic-ing of BDNF, a kinesin-1 cargo protein (Dompierre et al., 2007).pecific HDAC6 inhibition can also enhance mitochondrial traffic-ing in cultured hippocampal neurons (Chen et al., 2010). HDAC6as been suggested to be neuroprotective as well (Pandey et al.,007b; Du and Jiao, 2011). In a Drosophila melanogaster model ofpinobulbar muscular atrophy, and in Drosophila with mutationshat impair proteosome function, HDAC6 overexpression protectedgainst neurodegeneration (Pandey et al., 2007a,b). Work by theseuthors suggests that HDAC6 is critical for autophagic degradationf noxious proteins (Pandey et al., 2007a).

As discussed, in normal mice inhibition of class I HDAC func-ion benefits learning and memory, and several exciting recenttudies have translated this phenomenon to rodent models ofeurodegenerative disease (Fischer et al., 2007; Ricobaraza et al.,009; Graff et al., 2012). Beneficial effects of central or peripheralreatments with HDAC inhibitors on retention of fear associa-ions have been observed in mouse models of Alzheimer’s diseaseFischer et al., 2007). Furthermore, HDAC inhibition can improveearning after traumatic brain injury in mice (Dash et al., 2009).iven the putative neuroprotective effects of HDAC inhibition it

s not clear if benefits are a result of enhanced cellular survivalr increasing the plastic potential of existing cells. A recent studyy Graff et al. (2012) using an Alzheimer’s model suggests the

atter. Using a p25 over-expressing mouse to model neurodegen-ration the authors show that HDAC2 is increased in degeneratingeurons, and the increase is responsible for suppressing geneselated to synaptic plasticity and memory formation. Short-hairpinediated knockdown of HDAC2 reinstated gene expression and

mproved learning, without improving neuronal survival (Grafft al., 2012).

Class II HDACs are important for adaptive behavioral responseso chronic stress, a known precipitating factor in many cases of

ajor depressive disorder (Kendler et al., 1999). Chronic socialefeat stress, a putative mouse model of depressive-like behav-

or, down-regulates HDAC5 mRNA in the nucleus accumbens, whilehronic treatment with the antidepressant imipramine increasesDAC5 expression in animals that have been subjected to the

ocial defeat paradigm (Renthal et al., 2007). By contrast, over-xpression of HDAC5 antagonizes imipramine’s antidepressantffects (Tsankova et al., 2006). Chronic injection of HDAC inhibitorsnto the nucleus accumbens prevented the social avoidance phe-otype typically seen in mice that have been socially defeatedCovington et al., 2009). Importantly, intra-accumbens HDAC inhi-ition had antidepressant action in the forced swim and sucrosereference tests, establishing that HDAC inhibition rescues sev-ral depressive-like symptoms induced by chronic stress (e.g.,nhedonia, behavioral despair, and reduced social interaction).sing gene microarrays the authors also demonstrated that chronicS-275 infusion into nucleus accumbens reversed the pattern

f gene expression observed following social defeat in a fashionimilar to chronic treatment with fluoxetine, a somewhat perplex-


ng observation considering that MS-275 does not inhibit classIa HDACs, and may implicate class I HDACs in the behavioralesponses. Recently it was reported that HDAC5 is decreased ineripheral white blood cells of depressed patients, along with

845

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HDAC2 (Hobara et al., 2010). It is not yet clear how this observa-

tion relates to the onset or maintenance of the depressive state.

Initial behavioral studies in HDAC6 mutant mice suggest that

this class IIb HDAC may also be important for mood regulation.

Constitutive deletion of HDAC6 induces hyperactivity in a novel

environment, but not in the home cage. Furthermore deletion of

HDAC6 reduces anxiety, and has antidepressant effects (Fukada

et al., 2012).

The transition from recreational drug use to addiction may

involve enduring changes in gene expression patterns in brain

regions critical for processing rewarding stimuli (Kumar et al.,

2005; Wallace et al., 2008). Consistent with this hypothesis is the

observation that drug-induced alterations in chromatin structure

occur in the nucleus accumbens, a forebrain region that is crit-

ical for reward processing, and these alterations are dissociable

depending on the temporal nature of drug exposure. Similar to

what is observed following stressors, rats given acute treatments

with cocaine display increased acetylation of H4 in the promoter

regions of the immediate early genes fosB and cfos, whereas chronic

exposure preferentially induces hyperacetylation of H3 around the

fosB, cyclin-dependent kinase 5 (CDK5), and BDNF gene promo-

ters (Brami-Cherrier et al., 2005; Kumar et al., 2005; Levine et al.,

2005). Interestingly, over-expression of HDAC4 in nucleus accum-

bens reverses the acetylation patterns as well as the behavioral

adaptations induced by chronic cocaine administration (Kumar

et al., 2005). Also, treatment with the non-specific HDAC inhibitors

TSA and sodium butyrate enhanced the locomotor activating effects

of cocaine, as well as preference for a cocaine-paired environment.

Another class II HDAC, HDAC5, has also been implicated in

mediating neural alterations that result from chronic exposure

to drugs of abuse. High levels of HDAC5 are expressed in the

nucleus accumbens, and Nestler and co-workers have shown that

genetic manipulations of HDAC5 in this brain region profoundly

influence an animal’s sensitivity to, and interactions with, cocaine

(Renthal et al., 2007). HDAC5 phosphorylation is increased in

mice with a history of cocaine administration as opposed to acute

experience. Furthermore, over-expression of HDAC5 in the accum-

bens diminished conditioned place preference for a cocaine-paired

environment, an effect that could be blocked by TSA treatment.

HDAC5 KOs exhibited the opposite phenotype, an enhanced sen-

sitivity to cocaine, provided the animals were chronically given

cocaine. HDAC5 KO mice displayed normal responses to acute

cocaine, suggesting that HDAC5 may be specifically important for

the behavioral transition from acute to chronic drug use. Through a

cAMP-dependent mechanism, acute cocaine, unlike chronic expe-

rience, dephosphorylates HDAC5, which lessens the rewarding

effects of cocaine exposure (Taniguchi et al., 2012). The dephospho-

rylation leads to nuclear accumulation of HDAC5 which colocalizes

with MEF2, an effect that is blocked by the inhibition of protein

phosphotase 2A.

A consistent finding is the effect of HDAC inhibition on the

learning of fear associations. Fear conditioning creates de novo

associative memories through the pairing of an initially innocu-

ous stimulus (a “conditioned stimulus”) such as an auditory tone

or a novel environment with a salient, biologically relevant stim-

ulus (“unconditioned stimulus”), for example, a mild footshock.

Posttraumatic stress disorder, anxiety disorders, and the develop-

ment of phobias are characterized by an inability to extinguish

fear responses. HDAC inhibition is a potentially relevant avenue

for treating these disorders, as they accelerate the extinction of

fear responses in animals (Lattal et al., 2007; Bredy and Barad,

2008). However, acute knockdown of HDAC1 in hippocampus has

also been reported to impair the rate of fear extinction (Bahari-

Javan et al., 2012), hence it remains unclear whether a blockade or


potentiation of class I HDAC activity would be most appropriate in 847

targeting disorders marked by maladaptive extinction processes. 848


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. Concluding remarks

As recently suggested by Haberland et al. (2009a,b) “one of theost perplexing aspects of HDAC biology is that pharmacologi-

al inhibition of HDAC activity provides a therapeutic benefit inuch a wide variety of disease states”. The overwhelming bene-ts observed following HDAC inhibition in a number of diverseontexts begs the question – should everyone be taking HDACnhibitors? In short – no, or at least not yet. The HDAC inhibitorsurrently available are not well tolerated when administeredhronically, and patients present with side effects including fatigue,iarrhea, and cardiac side effects (Marsoni et al., 2008), how-ver, HDAC inhibitors present with lower toxicity and fewer sideffects than most other cancer drugs (Minucci and Pelicci, 2006).eleterious cellular effects of HDAC inhibition have been noted,

ncluding apoptosis, dysfunctional activity of chaperone proteinse.g., HSP90), interference with tubulin assembly, induction ofeactive oxygen species, and inhibition of angiogenesis and adulteurogenesis (Glozak et al., 2005; Marsoni et al., 2008; Jawerkat al., 2010). In addition all HDAC inhibitors promote cell cyclerrest to some degree (an exception is HDAC6-selective inhibitors),owever, normal cells are more resistant than tumor cells to thepoptotic effects of HDAC inhibition, for reasons still unknownMinucci and Pelicci, 2006; Ocker, 2010).

Isoform-specific HDAC inhibitors have proven to be a chal-enge to develop. The majority of HDAC inhibitors used currentlynhibit multiple isoforms among classes I, II, and IV HDACs. HDACnhibitors are typically among the following structural classes:yclic peptides, depsipeptides, hydroxymates, and short-chain fattycids. Several HDAC inhibitors have been developed from naturallyccurring sources (e.g., luteolin from celery). A handful of inhibitorsave been developed that exhibit class I selectivity with nanomo-

ar potency, although they target several isoforms within the classe.g., MS-275 targets HDAC1, 2, and 3). Similarly, HDAC6-selectivenhibitors have been developed (e.g., tubacin), however in manyases these compounds exhibit a high degree of lipophilicity andre difficult to synthesize, rendering them more useful as tools foresearch (Dallavalle et al., 2012). All HDAC inhibitors function byhelating the zinc ion at the HDAC active site, however, a highegree of structural homology at the enzyme active site of theDACs presents a hurdle that must be overcome to achieve the

ignificant clinical promise in manipulating individual HDAC iso-orms (Balasubramanian et al., 2009; Dallavalle et al., 2012). Mostnhibitor compounds consist of 3 domains, the zinc binding domain,

cap group which interacts with amino acids at the N-acetylatedysine binding channel, and a linker region that connects the zincinding and cap domains. Given the homology between HDACs inhe zinc-binding active site, it has been suggested that modifyinghe cap group may be the most promising strategy for ultimatelyeveloping isoform specific compounds (Suzuki, 2009; Dallavallet al., 2012).

This review has highlighted how manipulation of individualDACs can have diverse phenotypic outcomes, most notably forognitive function and neurodegeneration. Distinct and opposingffects of class I versus class II HDAC inhibition argue against aledgehammer pharmacological approach, although the benefits ofroad HDAC inhibition undoubtedly outweigh the costs in some cir-umstances (e.g., cancer). Study of HDAC biology is still in relativenfancy, however in the future domains in health-care and psychi-try will benefit from the development of better pharmacologicalools to manipulate the activity of individual HDACs in the brain.


cknowledgements

We thank members of the Monteggia laboratory for discussionsnd comments on the manuscript. This work was supported by


NIH grants MH081060 (LMM) as well as funding from the Brain

& Behavior Research Foundation (LMM; MJM).

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unique functional roles for class i and class ii histone deacetylases in central nervous system...

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